TOP
닫기
Search 닫기
Advanced Search Quick links
· Most Cited · Most Read · On-line First · Archives · Go to e-Submission

Minireview

Split Viewer

Mol. Cells 2019; 42(8): 569-578

Published online August 23, 2019

https://doi.org/10.14348/molcells.2019.0007

© The Korean Society for Molecular and Cellular Biology

Transient Receptor Potential Channels and Metabolism

Subash Dhakal and Youngseok Lee*

Author Info. +

Department of Bio and Fermentation Convergence Technology, Kookmin University, BK21 PLUS Project, Seoul 02707, Korea

Correspondence to : ylee@kookmin.ac.kr

Received: January 20, 2019; Revised: July 27, 2019; Accepted: August 13, 2019

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Go to

Transient receptor potential (TRP) channels are nonselective cationic channels, conserved among flies to humans. Most TRP channels have well known functions in chemosensation, thermosensation, and mechanosensation. In addition to being sensing environmental changes, many TRP channels are also internal sensors that help maintain homeostasis. Recent improvements to analytical methods for genomics and metabolomics allow us to investigate these channels in both mutant animals and humans. In this review, we discuss three aspects of TRP channels, which are their role in metabolism, their functional characteristics, and their role in metabolic syndrome. First, we introduce each TRP channel superfamily and their particular roles in metabolism. Second, we provide evidence for which metabolites TRP channels affect, such as lipids or glucose. Third, we discuss correlations between TRP channels and obesity, diabetes, and mucolipidosis. The cellular metabolism of TRP channels gives us possible therapeutic approaches for an effective prophylaxis of metabolic syndromes.

Keywords metabolic diseases, metabolism, transient receptor potential channel

INTRODUCTION

Go to

Transient receptor potential (TRP) channels are highly conserved transmembrane protein channels present in organisms, ranging from worms to mammals (Venkatachalam and Montell, 2007). These cationic channels were first characterized in the vinegar fly, Drosophila melanogaster. While a visual mechanism using forward genetic screening was being studied, a mutant fly showed a transient response to constant light instead of the continuous electroretinogram response recorded in the wild type (Cosens and Manning, 1969). Therefore, the mutant was named as transient receptor potential (trp). In the beginning, researchers had spent two decades discovering the trp locus with the germ-line transformation of the genomic region (Montell and Rubin, 1989). Using a detailed structural permeation property analysis in light-induced current, the TRP channel was confirmed as a six transmembrane domain protein, bearing a structural resemblance to a calcium-permeable cation channel (Montell and Rubin, 1989). This channel system shows structural resemblance with voltage-gated cation channels but largely different in composition of the positively charged amino acid residues which determines voltage sensing (Morita et al., 2007). So far, about 100 trp genes have been reported in many animals (Nilius et al., 2007). TRP channels are subdivided into two groups and seven subfamilies: Group 1 includes TRPC (canonical, C1–C7), TRPV (vanilloid, V1–V6), TRPM (melastatin, M1–M8), TRPA (ankyrin, A1), and TRPN (NOMP-like). Group 2 includes TRPP (polycystin, P1–P5) and TRPML (mucolipin, ML1–ML3) (Nilius and Owsianik, 2011).

The ancient TRP channels which are present in protists, chlorophyte algae, choanoflagellates, yeasts, and fungi are primarily involved in chemosensory, thermosensory, or mechanosensory functions (Matsuura et al., 2009; Wu et al., 2010). Many of these functions are remarkably conserved and can be found in various groups, including protists, worms, flies, and humans (Montell, 2005). TRP channels are involved in diverse physiological functions, ranging from sensation (pheromone signaling, visual, auditory, and taste transduction, nociception, and temperature sensation) to motility (muscle contraction and vaso-motor control). Furthermore, TRP channels are the key participants in the regulation of gut motility, mineral absorption, blood circulation, bladder and airway hypersensitivities, body fluid balance, cell growth, and survival (Nilius et al., 2007; Uchida et al., 2017).

Metabolism and glucose homeostasis are tightly regulated processes (Williams and Elmquist, 2012). The central nervous system (CNS) incorporates both central and peripheral signals for the coordinated control and modulation of food consumption, glucose homeostasis, and energy expenditure. However, in vivo study of physiological roles of TRP channels expressed in the CNS is still insufficient. Around 30 TRP channels are documented to be expressed in the digestive system. They are involved in taste, gastrointestinal movement, absorption, secretion, and maintenance of mucosal homeostasis (Holzer, 2011; Lee et al., 2016). Interestingly, involvement of various hormones and neurotransmitters alter the activity of channel system that controls the neuronal functions in the central regulation of metabolism (Brownstein, 1977). Combined studies using mouse genetics, together with neuroanatomical methods and electrophysiological examination, have provided new findings about the roles of various ion channels that modulate neurons associated with metabolism and related disorders (Sohn et al., 2013).

TRP channels are present in various metabolically important tissues. They are widely expressed in the pancreatic cells, liver, gastrointestinal tract (Yu et al., 2016), skeletal muscle, kidney, adipose tissue, heart, vasculature, and nervous system (Zhu et al., 2011). Although TRP channels and their ligands are potential targets to treat obesity and diabetes in the field of metabolic diseases (Nilius and Szallasi, 2014), their roles in many metabolic processes are still controversial and being studied. Here we discuss the role of TRP channels in metabolism and suggest numerous avenues for future study.

TRP CHANNELS IN METABOLISM

Go to

Members of the TRP channels play important physiological roles and can be observed in cells in different metabolic states. They work as gatekeepers for the trans-cellular transport of several cations, including Ca2+ and Mg2+, but their biological roles are diverse (Table 1) (Nilius and Owsianik, 2011).

TRPA

TRPA1 is a receptor for a broad range of environmental oxidants and irritants and has a central role in pain and other preclinical conditions (Julius, 2013). It is directly activated by cinnamaldehyde, allyl isothiocyanate (AITC), allicin, formalin, and icilin (Bessac and Jordt, 2008; Macpherson et al., 2007; Trevisani et al., 2007). In association with cinnamaldehyde, TRPA1 drives insulin and ghrelin secretion, enhances insulin sensitivity in the CNS and reduces the deposition of fat in the liver. Supplementing AITC with a high-fat diet causes less weight gain compared with high-fat diet alone in mouse model (Ahn et al., 2014). Drosophila TRPA1 (dTRPA1) is highly expressed in the posterior dorsal ganglion of the fly brain and the axon bundles of the place are sent to the sub-esophageal zone, which is a primary center to regulate feeding (Lee, 2013). This indicates possible direct control in metabolism of dTRPA1 in brain. Non-targeted metabolomic profiling revealed that mutations in dTRPA1 had a direct effect on the free fatty-acid metabolism and methionine salvage pathway. Furthermore, trehalose is a sugar associated with cellular processes for heat protection. This process is slightly upregulated in a trpA1 mutant background (Lee et al., 2016). TRPA1 has a role in enteroendocrine L-cells of the intestine. The gut hormone, glucagon-like peptide 1 (GLP-1) has a crucial role in glucose metabolism. It acts via changing insulin secretion on the gut–brain axis. Administration of TRPA1 into the duodenum resulted in GLP-1 secretion from these cells. So higher levels of GLP-1 can be an alternative hallmark in antidiabetic therapy (Smeets and Westerterp-Plantenga, 2009). TRPA1 is also expressed in enterochromaffin cells that contain cholecystokinin (CCK). The activation of TRPA1 causes satiety in mice via CCK secretion (Nozawa et al., 2009). Methyl syringate, one of the TRPA1 agonists, decreases food ingestion and gastric emptying in mouse models (Kim et al., 2013). However, TRPA1 is also expressed in the tongue of mammals and insects (Kim et al., 2010; Xiao et al., 2008). It is possible that TRPA1 agonists can directly activate taste receptor cells to reduce ingestion. So it is combinatory effect in pheripheral as well as internal sensors.

TRPV

The TRPV channel subfamily has six members categorized into two groups: TRPV1–V4 and TRPV5–V6. TRPV1–V4 consists of the thermo-TRPs that are triggered by specific temperature threshold. Although TRPVs that are thermosensitive seem to function in sensing temperature changes, these channels are also present in tissues where dramatic temperature swings are prevented by thermoregulatory homeostasis. Thus, temperature may perform a permissive rather than essential role in controlling the activity of these TRPs (Lyall et al., 2004; Moqrich et al., 2005). TRPV5 and TRPV6 have a role to reabsorb Ca2+ from the kidney and intestine, respectively (Nijenhuis et al., 2005).

TRPV1 has a role in potential sensory nerves that innervate into pancreatic islets and adipose tissues for insulin production. These channels are expressed in several neuronal (from olfactory, basal ganglion to cerebellum) and non-neuronal (buccal cavity, intestine, stomach, liver, and pancreas) cells (Nilius and Szallasi, 2014; Seabrook et al., 2002). TRPV1 channel is activated by temperature threshold around 42°C, and hot pepper ingredient, capsaicin. Ingestion of capsaicin, the well-known TRPV1 agonist, prevents diet-induced obesity in mouse models (Kang et al., 2010). Adipose tissue expresses TRPV1, but the tissue isolated from obese animals including humans displayed reduced expression level of TRPV1 (Chu et al., 2003; Zhang et al., 2012). TRPV1 knock-out (KO) mice developed age-associated obesity and hypo-metabolism (Wang and Siemens, 2015). However, recent findings have indicated that the prevention of obesity as beneficial effects seem to be minute and would in all probability require daily long-term intake of capsaicin (Saito and Yoneshiro, 2013; Whiting et al., 2014). While consuming a standard chow diet, TRPV1 KO mice showed normal insulin sensitivity, with comparable glucose metabolism rates to wild-type mice (Lee et al., 2015). Interestingly, TRPV1 KO mice were also protected from obesity caused by diet and exhibited an increased longevity, which correlated with the prolongation of a juvenile metabolic profile (Motter and Ahern, 2008).

In addition, TRPV1 is found to participate in multifaceted metabolic functions in various other tissues, including the adipose tissue, hypothalamus, and the gastrointestinal tract (Baboota et al., 2014). However, the exact roles underlying their protective functions in these tissues remain obscure. Relying on the metabolic state and cell type, TRPV1 has been a positive inducing factor for metabolic homeostasis. Activation of TRPV3 triggers inhibition of the phosphorylation of insulin receptor substrate-1 (IRS-1) and suppression of PPAR-γ, thus preventing lipid accumulation and adipogenesis (Bang et al., 2010; 2011; Ye et al., 2012). In brown adipose tissue (BAT), activation of TRPV4 negatively operates oxidative metabolism (Ye et al., 2012). The loss of TRPV4 results in a rise of oxidative potential in skeletal muscle by a compensatory regulatory mechanism (Kusudo et al., 2011). Interestingly, creating TRPV4 KO mice or antagonizing TRPV4 by pharmacologic blockade with glibenclamide elevates thermogenesis in adipose tissue and protects against adipose inflammation, diet-mediated obesity, and insulin resistance. TRPV4 in adipose tissue boosts pro-inflammatory cytokines (Bang et al., 2012; Ye et al., 2012).

TRPM

The TRPM subfamily is composed of eight members, which are categorized into three groups based on their structural homology: TRPM1/3, TRPM4/5, and TRPM6/7. TRPM2 and TRPM8 have relatively low sequence homology with the others and therefore they are not included in the group. TRPM2, TRPM6, and TRPM7 are distinctive among other TRPM channels because they have active enzyme domains in their C-termini merged to their transmembrane domains (Moran et al., 2011; Walder et al., 2009). TRPM2, TRPM3, TRPM4, and TRPM5 have been distinguished to contribute in the regulation of metabolism (Zhu et al., 2011).

TRPM2, TRPM3, TRPM4, and TRPM5 are present in rodent insulinoma cells and mouse islets. TRPM2, TRPM4, and TRPM5 have a role in the regulation of insulin secretion. TRPM2 and TRPM4 channels are present in insulin-producing pancreatic β-cells, and expression of dominant negative forms of TRPM4 and TRPM2 small interfering RNAs (siRNAs) decreases insulin secretion from the β-cells (Cheng et al., 2007; Grand et al., 2008; Kraft et al., 2006; Togashi et al., 2006). TRPM5 is also important for Ca2+-activated cation channels in β-cells and GLP-1 secreting L-cells. Much like the TRPV1, the TRPM8 channel has a role in adipocytes (Fernandes et al., 2012; Parks et al., 2010; Rossato et al., 2014). Menthol is a known TRPM8 agonist which induces hyperactivity and suppresses diet-induced weight gain (Jiang et al., 2017; Peier et al., 2002). Menthol amplifies uncoupling protein 1 (UCP-1) expression in BAT in a dose-dependent way. However, this effect disappears in TRPM8 KO mice. Mice can be prevented from diet-induced obesity through prolonged dietary menthol supplements. In humans, TRPM8 activation can induce the browning of white adipose tissue (WAT browning), possibly by accelerating energy consumption (Rossato et al., 2014).

TRPM2 KO mice have deficits in insulin production under both high-fat or normal diet (Uchida and Tominaga, 2011). TRPM2 is broadly expressed in organs including the heart, brain, kidney and the immune system. It also functions as an oxidative stress sensor (Jang et al., 2014; Perraud et al., 2005). Moreover, TRPM2, TRPM4, and TRPM5 are controlled via CNS and have roles in neuronal activation, neurodegeneration, and cell death (Ramsey et al., 2006).

FUNCTIONAL CHARACTERISTICS OF TRP CHANNELS

Go to

Lipid metabolism

TRP channels have been shown to be key regulatory proteins involved in the process of lipid metabolism and energy homeostasis (Zhu et al., 2011). TRPV1 activation by capsaicin induces decreased triglyceride amounts in 3T3-L1 pre-adipocytes during adipogenesis. Similarly, capsaicin reduces dietary high-fat-induced hypertriglyceridemia in rats by exhibiting higher lipoprotein lipase movement in adipose tissues (Tani et al., 2004). Depending on the membrane lipid content, the localization, and function of TRP channel can be controlled. When methyl-β-cyclodextrin was treated in rat arteries as the cholesterol acceptor, membrane cholesterol is reduced, and trpC1 expression level is decreased (Bergdahl et al., 2003). Similarly, cholesterol depletion in adult rat DRGs reduces TRPV1 levels in membrane, which induces decrease of TRPV1 currents mediated by proton or capsaicin (Liu et al., 2006). Furthermore, lysophosphatidylcholine (LPC) derived from phosphatidylcholine in cell membrane activates TRPC6 in cultured human corporal smooth muscle cells. LPC is one of major phospholipids of oxidized low density lipoprotein (LDL), which is an active pro-inflammatory lipid in pathological conditions (Rabini et al., 1994). Moreover, LPC and lysophosphatidylinositol (LPI) are able to induce TRPV2 activation. This activation mediated by Gq/Go and phosphatidylinositol-3,4 kinase (PI3,4K) signaling, seems to be mostly attributable to TRPV2 localization to the plasma membrane. It is highly dependent on the lysophospholipid head group and the length of the side-chain. In prostate cancer, metastasis of the cells is increased by TRPV2 activation by LPC and LPI (Monet et al., 2009). This may suggest a pathological role of TRPV2. Furthermore, 7-ketocholesterol, as a component of oxidized LDL, induces TRPC1 translocation to lipid rafts, activation of the channel, and increased calcium influx (Berthier, 2004).

Some studies have highlighted differences in intracellular Ca2+ concentration among normal and insulin-resistant cardiomyocytes by the application of bipolar lipids. Exogenous polyunsaturated fatty acids (PUFAs) bypass endogenous synthesis of PUFAs by eliciting TRPV1-dependent Ca2+ inward currents in sensory neurons (Kahn-Kirby et al., 2004; Lanner et al., 2008). Both cholesterol and sphingolipids as raft-enriched lipids may have effects on TRP channel activity, either via direct protein-lipid interactions or by affecting the physical properties of the lipid bilayer (Dart, 2010). Lipid signaling and lipotoxicity are strongly connected with oxidative metabolism. As a result, lipid agonists or modulators of TRPC channels are subject to oxidative modification (Svobodova and Groschner, 2016).

Glucose metabolism

Hyperglycaemia significantly increases TRPC6 in platelets, whereas expression of other TRPC members remain the same (Liu et al., 2009). GLUT4 is a glucose transporter protein, which is highly expressed in mammalian adipose tissues and skeletal muscles (Huang and Czech, 2007). Unlike other cohorts of glucose transporters, GLUT4 responds efficiently to insulin. A variety of genetically engineered mouse models have been used to demonstrate the role of GLUT4 in maintaining whole body metabolism, including glucose homeostasis in muscles and energy sensors in adipocytes. However, GLUT4 KO mice show normal fat mass and adipocyte size, and normal glucose uptake in adipose tissues. GLUT4 is an energy sensor rather than a main regulator of glucose homeostasis in adipocytes (Yoshioka et al., 1995). Interestingly, TRPV1 KO mice showed longer life spans, with juvenile metabolic phenotypes, when their diet was supplemented with capsaicin, suggesting TRPV1 may cause diet-induced obesity in mice (Riera et al., 2014). In contrast, TRPM8 activation via diet supplements in mice was protective against diet-induced obesity (Rossato et al., 2014).

METABOLIC SYNDROME

Go to

TRP channels are widely present in the tissues including adipocytes, endothelial cells and vascular smooth muscles. So the deficits of TRP channels are highly related to numerous diseases and specifically related with the progression of varied cardiovascular diseases (Nilius et al., 2007). This explains their widespread functions. However, because they are widely distributed, disturbance in or alterations in expression of TRP channels may induce the development of metabolic syndrome (Table 2). Multiple channels such as TRPV1, TRPC3, TRPC6, and TRPC7 are activated essentially by diacylglycerol, whereas other TRPCs such as TRPC4, TRPC5, and TRPC6 are mainly activated after exhaustion of intracellular sarcoendoplasmic stores (Nilius et al., 2007). TRP channels may be directly affected by the agonists that were involved in the pathology of metabolic syndrome. For instance, angiotensin receptors are activated by angiotensin II. Series of ligand dependent activation cascade finally lead to the production of inositol triphosphate and diacylglycerol from phosphoinositide. These are the keys to open TRP channels, as elevation of diacylglycerol and depletion of inositol trisphosphate stores activate TRP channels (Bottari et al., 1993). The hetero-multimeric composition and expression of TRP channels maintain balance in the intracellular calcium homeostasis via transmembrane calcium influx. These functional alterations may develop metabolic syndromes (Liu et al., 2008).

Obesity

Obesity is the abnormal increase in body weight, as a sign of many of metabolic syndromes (Grundy, 2004). The TRPV1 channel is a key regulator of pre-adipocytes, appetite regulation, fat distribution, and obesity-induced chronic inflammatory responses. Both endogenous agonists (N-arachidonoyl dopamine and anandamide) and exogenous agonists (capsaicin and resiniferatoxin) may influence TRPV1 channel activity (Kumar et al., 2013). Application of capsaicin prevents adipogenesis and obesity in both mice and humans. Capsaicin increases intracellular calcium in pre-adipocytes but not in mature adipocytes, which is highly dependent on TRPV1 expression between pre-adipocytes and mature adipocytes (Xu et al., 2005; Zhang et al., 2007). However, when mice were fed on a high-fat diet, weight gain did not differ between TRPV1 KO and wild-type mice (Marshall et al., 2012). Moreover, ingestion of capsaicin with a high-fat diet did not block obesity in TRPV1 KO mice, although it affected obesity in wild-type (Zhang et al., 2007). This finding may be explained by another study that showed the phenotype of TRPV1 KO mice is dependent on age and environmental variables that have direct impact on thermoregulation (Wanner et al., 2011).

TRPV1 is expressed in visceral adipose tissues expressed in visceral as well as pre-adipocytes. When mice is fed with high sugar (high diet food) supplemented with TRPV1 agonist mono-acyl glycerol, it prevents white fat accumulation, activating mitochondrial UPC1 in BAT. Comparing obese male mice with their lean counterparts, the level of TRPV1 is alleviated in visceral tissues. Moreover, ingestion of capsaicin with a high fat diet did not block obesity in TRPV1 KO mice, although it affected obesity in wild type (Zhang et al., 2007). This activation of TRPV1 leads to PPAR-γ activation, nuclear factor NF-kB inactivation, the secretion of pro-inflammatory mediators by macrophage activation, and inhibition of obesity-associated macrophage migration. The obesity induced chronic inflammatory responses have major role in the developmental process of atherosclerosis and type II diabetes mellitus (T2DM) (Masuda et al., 2003). Endogenous TRPV1 agonist, N-oleoylethanolamide activates vagal sensory afferent neurons that regulate calorie intake and appetite. This phenomenon is investigated only in wild type mice, because only wild type mice showed decreased food consumption, suggesting that TRPV1 activation may control appetite (Wang et al., 2005).

Some TRPV members (V1–V4) have been proven to play pivotal roles in adipocytes. TRPV3 is highly expressed in adipocytes, and its activation prevents lipid buildup and adipogenesis (Cheung et al., 2015; Qin et al., 2008). In contrast, only TRPV1, TRPV2, and TRPV4 may have roles in 3T3-F442A pre-adipocytes. TRPV4 is highly expressed in this cell line, which confirms previous observation that exhibit TRPV4 expression in adipose tissue (Liedtke et al., 2000). Subcutaneous adipose tissue of TRPV4 KO mice showed higher UCP1 levels compared with control mice. Taken together, TRPVs results in having significant functions in adipocytes (Suzuki et al., 2003; Zsombok and Derbenev, 2016).

TRPM5 is a common downstream ion channel in type 2 taste receptor cells for GPCRs, which sense the basic tastes of sweet, umami, and bitter (Sprous and Palmer, 2010). Genetic changes in TRPM5 completely impaired the ability of mice to detect not only various tastes but also fat (Liu et al., 2011). Blocking TRPM5 in taste cells reduces appetite, so it can be a strategy to lose weight (Palmer and Lunn, 2013; Palmer et al., 2010; Sprous and Palmer, 2010). Quinine as a TRPM5 blocker induces weight loss in a mouse model (Cettour-Rose et al., 2013). Similarly, but inversely, levels of the fat hormone, adiponectin, are correlated with the amount of fat. Thus, overexpression of adiponectin increases energy expenditure and as a result, induces a lean body type. Blocking TRPC5 channels results in increase of plasma adiponectin, which can be beneficial to patients with metabolic disorders such as obesity and T2DM (Palmer and Lunn, 2013).

Diabetes

It is experimentally proven that several TRP channels have a practical role in the onset of diabetes mellitus (Liu et al., 2008). Among different TRPVs, TRPV1 has been found to control islets inflammation and insulin resistance by activating its associated pancreatic sensory neurons. Ablating TRPV1-associated pancreatic sensory neurons in diabetes-prone mice prevents developing diabetes and insulitis. This indicates that pathogenesis of type I diabetes mellitus is associated with TRPV1 activation (Razavi et al., 2006). Insulin signaling promotes mitochondrial oxidative capacity and ATP production. TRPA1 is abundant in rat pancreatic β cells (Colsoul et al., 2013). TRPA1 agonists such as mustard oil and 4-hydroxy-2-nonenal induce insulin secretion in pancreatic β cells. Furthermore, the TRPA1 antagonist including HC-030031 hinders insulin release induced by glucose increase. This provides the evidence that TRPA1 has a direct role to control insulin secretion (Leibiger et al., 2002).

TRPM2 activation induces calcium increase into pancreatic islets, and increases in the level of cyclic ADP-ribose. This results in regulating insulin secretion (Togashi et al., 2006). Reactive oxygen species (e.g., H2O2), glucose, and incretins are stimuli for the activation of TRPM2 (Uchida and Tominaga, 2011). TRPM2 KO mice are more sensitive to insulin because of increased glucose metabolism in their heart arising from the phosphorylation of elevated Akt and glycogen synthase kinase 3. TRPM2 KO mice also reduce inflammation in the adipose tissue and liver (Zhang et al., 2012). These evidences demonstrate that TRPM2 has a role in metabolism. Expression of TRPM2, TRPM4, and TRPM5 has been found in human islets of Langerhans, suggesting that they may regulate pancreatic function and insulin secretion (Colsoul et al., 2013; Takezawa et al., 2006).

Mucolipidosis

Lysosomal storage disorders are metabolic diseases characterized by a deficiency in the enzymes that are important for vesicular lipid, carbohydrate, and protein metabolism (Futerman and Van Meer, 2004). Four types of mucolipidosis have been identified based on their physiology and pathophysiology (David-Vizcarra et al., 2010). Mucolipidosis type IV (MLIV) is an autosomal recessive disorder, generated by mutations in transient receptor potential mucolipin 1 (TRPML1). In MLIV, TRPML1, a vesicular Ca2+ release channel, is non-functional. TRPML1 contributes to the fusion of amphisomes with lysosomes. Other types of mucolipidosis are caused by non-functional metabolic enzymes. These include mucolipidosis I (sialidosis), caused by aberrant sialidase, and mucolipidosis II and III, caused by mutated N-acetylglucosamine-1-phosphotransferase (Shen et al., 2012; Tiede et al., 2005; 2006). In Drosophila, a null mutation of trpml leads to pupal lethality, when the flies count to autophagy for nutrition. This pupal lethality is caused by reduced targets of rapamycin complex 1 (TORC1) signaling (Venkatachalam et al., 2013). This indicates that cellular amino acid starvation is one of the fundamental causes of toxicity in the TRPML deficiency. It raises the intriguing feasibility that neurological disorder in MLIV patients may therefore stem from amino acid deprivation. A high-protein diet can reduce pupal lethality and increase the amount of acidic vesicles. However, further inhibition of TORC1 activity by administering rapamycin worsens the trpml mutant phenotype. The severity of MLIV might be decreased with a high-protein diet (Wong et al., 2012).

CONCLUSION AND FUTURE PERSPECTIVES

Go to

TRP channels possess various metabolic functions which are thought to be key targets for different physiological processes. Glucose and lipid metabolism are the central pathways that maintain energy balance, thermal regulation, and control of the metabolome. Their dysfunction can cause metabolic diseases including obesity, diabetes, and mucolipidosis. The severity of these disorders can be diminished by the consumption of supplementary foods, such as capsaicin. However, the precise target of this supplementary dietary intake is not clearly understood because multiple tissues, such as adipose, pancreatic, and even CNS tissues may be modulated by these supplements. A systemic analysis would be required to reveal more of these mechanisms. Analysis of TRP channel mutated animals with regard to their metabolomes would help us to further understand TRP channel functions and related pathogenesis.

ACKNOWLEDGMENTS

Go to

S.D. was supported by the Global Scholarship Program for Foreign Graduate Students at Kookmin University in Korea. This work is supported by grants to Y.L. from the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B03931273 and NRF-2018R1A2B6004202).

TABLES

Go to
Table 1.

Receptors, activators and inhibitors of metabolic TRP channels

Subfamily Locus Activators Inhibitors Functions References
TRPV
 TRPV1 Sensory neurons, brain, spinal cord, keratinocytes, pancreas, tongue, and bladder Cannabigerol, capsaicin, gingerol, lysophosphatidic acid, piperine, N-oleoyldopamine, palmitoylethanol-amide, and vanillotoxin Capsazepine, iodo-resinifera toxin, resolvin D2 thapsigargin, yohimbine, and BCTC Taste, salivary secretion, thermoregulation, intestinal ion and fluid secretion, gastric hormone release, and insulin release (Chu et al., 2003; Parks et al., 2010; Seabrook et al., 2002)
 TRPV2 Brain, spinal cord, sensory neurons, spleen, and GI-tract Camphor, incensole acetate, and lysophosphatidylcholine Tranilast Thermoregulation, insulin release, and glucose homeostasis (Qin et al., 2008)
 TRPV3 Brain, sensory neurons, and tongue Farnesyl pyrophosphate and menthol Isopentenyl pyrophosphate and resolvin D1 Taste, thermoregulation, and GI cancer (Bang et al., 2010; 2011; Moqrich et al., 2005)
 TRPV4 Brain, sensory neurons, kidney, heart, liver, spleen, and inner ear Citric acid, dimethylallyl pyrophosphate, apigenin, and 4α-phorbol 12, 13-de decanoate Resolvin D1, HC-067047, and RN-1734 Thermoregulation and pain (Bang et al., 2012; Suzuki et al., 2003)
TRPM
 TRPM2 Brain, pancreas liver, and heart ADP-ribose and cyclic ADP-ribose Clotrimazole, N-(p-amylcinnamoyl) anthranilic acid, and econazole Insulin secretion, diabetes, obesity, and CNS disorder (Kraft et al., 2006; Perraud et al., 2005)
 TRPM4 Pancreas, colon, bladder, and heart BTP2 9-phenanthrol and flufenamic acid Insulin release and bladder function (Grand et al., 2008; Takezawa et al., 2006)
 TRPM5 Brain, taste coil, pancreas, GI-tract, liver, and tongue Rutamarin and steviol glycosides NSAID drugs, nicotine, tri-phenyl phosphine oxide, and 2-APB Taste, gastric hormone secretion, and insulin release (Palmer et al., 2010)
 TRPM8 Sensory neurons, liver, stomach, prostate, and bladder Menthol, linalool, geraniol, hydroxycitronellal, WS-3, and frescolat MGA AMTB, BCTC, benzimidazoles, and 5-benzyloxytrypamine Taste and thermoregulation (Parks et al., 2010; Peier et al., 2002)
TRPA
 TRPA1 PNS, hair cells, and enter-endocrine cells 15-deoxy-Δ12, 14-PGJ2, 4-hydroxynonenal, 4-oxononenal, and methylglyoxal Camphor, menthol, resolvin D1, and resolvin D2 Taste, thermoregulation, and gastric hormone release (Macpherson et al., 2007; Xu et al., 2005)
 TRPML2 CNS, pancreas, and intracellular ion channels SF-51, ML-SA1, SID24801657, and SID24787221 Adenosine deaminase (ADA) Mucolipidosis (Shen et al., 2012)

Table 2.

Involvement of TRP channels in each metabolic syndrome

Subfamily Receptor Functions in obesity Functions in diabetes Functions in mucolipidosis References
TRPV TRPV1 Reduction in adipogenesis, appetite control, fat distribution, obesity-induced chronic inflammatory responses, and TRPV1 activation increase liver function Islets inflammation and insulin resistance, progression to T1DM - (Zhang et al., 2007)
TRPV2 TRPV2 activation negatively regulate BAT differentiation, reduce lipid accumulation, KO mice has more WAT with HFD induced obesity TRPV2 inhibition cause glucose induced insulin secretion - (Suzuki et al., 2003; Uchida et al., 2017)
TRPV3 Activation prevent lipid build-up and adipogenesis - - (Cheung et al., 2015)
TRPV4 Regulate UPC1 level in subcutaneous adipose tissue, negatively regulate oxidative metabolism, TRPV4 KO protect from adipose inflammation, diet-mediated obesity, and insulin resistance - - (Ye et al., 2012)
TRPML TRPML1 & TRPML2 - - trpml mutation causes pupal lethality, autophagy for nutrition, amino acid deprivation. Impairment in vascular carbohydrate, lipid and protein metabolism (Venkatachalam et al., 2013)
TRPM TRPM2 TRPM2 KO are resistant to diet induced obesity and inflammation Increase calcium level, induce insulin secretion from pancreatic islets, KO reduce inflammation in adipose tissue and liver - (Zhang et al., 2012)
TRPM3 - Regulate zinc level, trigger insulin secretion from beta-cells - (Colsoul et al., 2013)
TRPM4 - Glucagon synthesis from alpha cells, indirect role in insulin synthesis - (Colsoul et al., 2013)
TRPM5 Basic taste regulator, control appetite and obesity Increase insulin secretion and glucose tolerance, regulate plasma insulin level - (Palmer et al., 2010)
TRPM6 - Balance serum magnesium level, reduce possibility of T2DM - (Walder et al., 2009)
TRPM8 TRPM8 activation induces browning of WAT, induces UPC1 expression in BAT - - (Rossato et al., 2014)
TRPA TRPA1 Activation cause satiety and control obesity Activation induce insulin secretion from beta cells - (Macpherson et al., 2007)

REFERENCES

Go to
  1. Ahn, J., Lee, H., Im, S.W., Jung, C.H., and Ha, T.Y. (2014). Allyl isothiocyanate ameliorates insulin resistance through the regulation of mitochondrial function. J Nutr Biochem. 25, 1026-1034.
    Pubmed CrossRef
  2. Baboota, R.K., Singh, D.P., Sarma, S.M., Kaur, J., Sandhir, R., Boparai, R.K., Kondepudi, K.K., and Bishnoi, M. (2014). Capsaicin induces “brite” phenotype in differentiating 3T3-L1 preadipocytes. PLoS One. 9, e103093.
    Pubmed KoreaMed CrossRef
  3. Bang, S., Yoo, S., Yang, T.J., Cho, H., and Hwang, S.W. (2010). Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3. J Biol Chem. 285, 19362-19371.
    Pubmed KoreaMed CrossRef
  4. Bang, S., Yoo, S., Yang, T.J., Cho, H., and Hwang, S.W. (2011). Isopentenyl pyrophosphate is a novel antinociceptive substance that inhibits TRPV3 and TRPA1 ion channels. Pain. 152, 1156-1164.
    Pubmed CrossRef
  5. Bang, S., Yoo, S., Yang, T.J., Cho, H., and Hwang, S.W. (2012). Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation. Br J Pharmacol. 166, 1433-1443.
    Pubmed KoreaMed CrossRef
  6. Bergdahl, A., Gomez, M.F., Dreja, K., Xu, S.Z., Adner, M., Beech, D.J., Broman, J., Hellstrand, P., and Swärd, K. (2003). Cholesterol depletion impairs vascular reactivity to endothelin-1 by reducing store-operated Ca2+ entry dependent on TRPC1. Circ Res. 93, 839-847.
    Pubmed CrossRef
  7. Berthier, L. (2004). Time and length scales in supercooled liquids. Phys Rev E. 69, 020201.
    Pubmed CrossRef
  8. Bessac, B.F. and Jordt, S.E. (2008). Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology. 23, 360-370.
    Pubmed KoreaMed CrossRef
  9. Bottari, S.P., de Gasparo, M., Steckelings, U.M., and Levens, N.R. (1993). Angiotensin II receptor subtypes: characterization, signalling mechanisms, and possible physiological implications. Front Neuroendocrinol. 14, 123-171.
    Pubmed CrossRef
  10. Brownstein, M. (1977). Neurotransmitters and hypothalamic hormones in the central nervous system. Fed Proc. 36, 1960-1963.
    Pubmed
  11. Cettour-Rose, P., Bezençon, C., Darimont, C., le Coutre, J., and Damak, S. (2013). Quinine controls body weight gain without affecting food intake in male C57BL6 mice. BMC Physiol. 13, 5.
    Pubmed KoreaMed CrossRef
  12. Cheng, W., Yang, F., Takanishi, C.L., and Zheng, J. (2007). Thermosensitive TRPV channel subunits coassemble into heteromeric channels with intermediate conductance and gating properties. J Gen Physiol. 129, 191-207.
    Pubmed KoreaMed CrossRef
  13. Cheung, S.Y., Huang, Y., Kwan, H.Y., Chung, H.Y., and Yao, X. (2015). Activation of transient receptor potential vanilloid 3 channel suppresses adipogenesis. Endocrinology. 156, 2074-2086.
    Pubmed CrossRef
  14. Chu, C.J., Huang, S.M., De Petrocellis, L., Bisogno, T., Ewing, S.A., Miller, J.D., Zipkin, R.E., Daddario, N., Appendino, G., and Di Marzo, V. (2003). N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J Biol Chem. 278, 13633-13639.
    Pubmed CrossRef
  15. Colsoul, B., Nilius, B., and Vennekens, R. (2013). Transient receptor potential (TRP) cation channels in diabetes. Curr Top Med Chem. 13, 258-269.
    Pubmed CrossRef
  16. Cosens, D. and Manning, A. (1969). Abnormal electroretinogram from a Drosophila mutant. Nature. 224, 285-287.
    Pubmed CrossRef
  17. Dart, C. (2010). Lipid microdomains and the regulation of ion channel function. J Physiol. 588, 3169-3178.
    Pubmed KoreaMed CrossRef
  18. David-Vizcarra, G., Briody, J., Ault, J., Fietz, M., Fletcher, J., Savarirayan, R., Wilson, M., McGill, J., Edwards, M., and Munns, C. (2010). The natural history and osteodystrophy of mucolipidosis types II and III. J Paediatr Child Health. 46, 316-322.
    Pubmed KoreaMed CrossRef
  19. Fernandes, E., Fernandes, M., and Keeble, J. (2012). The functions of TRPA1 and TRPV1: moving away from sensory nerves. Br J Pharmacol. 166, 510-521.
    Pubmed KoreaMed CrossRef
  20. Futerman, A.H. and Van Meer, G. (2004). The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol. 5, 554-565.
    Pubmed CrossRef
  21. Grand, T., Demion, M., Norez, C., Mettey, Y., Launay, P., Becq, F., Bois, P., and Guinamard, R. (2008). 9-phenanthrol inhibits human TRPM4 but not TRPM5 cationic channels. Br J Pharmacol. 153, 1697-1705.
    Pubmed KoreaMed CrossRef
  22. Grundy, S.M. (2004). Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab. 89, 2595-2600.
    Pubmed CrossRef
  23. Holzer, P. (2011). Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system. Pharmacol Ther. 131, 142-170.
    Pubmed KoreaMed CrossRef
  24. Huang, S. and Czech, M.P. (2007). The GLUT4 glucose transporter. Cell Metab. 5, 237-252.
    Pubmed CrossRef
  25. Jang, Y., Lee, M.H., Lee, J., Jung, J., Lee, S.H., Yang, D.J., Kim, B.W., Son, H., Lee, B., and Chang, S. (2014). TRPM2 mediates the lysophosphatidic acid-induced neurite retraction in the developing brain. Pflügers Arch. 466, 1987-1998.
    Pubmed CrossRef
  26. Jiang, C., Zhai, M., Yan, D., Li, D., Li, C., Zhang, Y., Xiao, L., Xiong, D., Deng, Q., and Sun, W. (2017). Dietary menthol-induced TRPM8 activation enhances WAT “browning” and ameliorates diet-induced obesity. Oncotarget. 8, 75114.
    Pubmed KoreaMed CrossRef
  27. Julius, D. (2013). TRP channels and pain. Annu Rev Cell Dev Biol. 29, 355-384.
    Pubmed CrossRef
  28. Kahn-Kirby, A.H., Dantzker, J.L., Apicella, A.J., Schafer, W.R., Browse, J., Bargmann, C.I., and Watts, J.L. (2004). Specific polyunsaturated fatty acids drive TRPV-dependent sensory signaling in vivo. Cell. 119, 889-900.
    Pubmed CrossRef
  29. Kang, J.H., Tsuyoshi, G., Han, I.S., Kawada, T., Kim, Y.M., and Yu, R. (2010). Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity. 18, 780-787.
    Pubmed CrossRef
  30. Kim, M.J., Son, H.J., Song, S.H., Jung, M., Kim, Y., and Rhyu, M.R. (2013). The TRPA1 agonist, methyl syringate suppresses food intake and gastric emptying. PLoS One. 8, e71603.
    Pubmed KoreaMed CrossRef
  31. Kim, S.H., Lee, Y., Akitake, B., Woodward, O.M., Guggino, W.B., and Montell, C. (2010). Drosophila TRPA1 channel mediates chemical avoidance in gustatory receptor neurons. Proc Natl Acad Sci. 107, 8440-8445.
    Pubmed KoreaMed CrossRef
  32. Kraft, R., Grimm, C., Frenzel, H., and Harteneck, C. (2006). Inhibition of TRPM2 cation channels by N-(p-amylcinnamoyl) anthranilic acid. Br J Pharmacol. 148, 264-273.
    Pubmed KoreaMed CrossRef
  33. Kumar, A., Goswami, L., and Goswami, C. (2013). Importance of TRP channels in pain: implications for stress. Front Biosci (Schol Ed). 5, 19-38.
    Pubmed CrossRef
  34. Kusudo, T., Wang, Z., Mizuno, A., Suzuki, M., and Yamashita, H. (2011). TRPV4 deficiency increases skeletal muscle metabolic capacity and resistance against diet-induced obesity. J Appl Physiol. 112, 1223-1232.
    Pubmed CrossRef
  35. Lanner, J.T., Bruton, J.D., Katz, A., and Westerblad, H. (2008). Ca2+ and insulin-mediated glucose uptake. Curr Opin Pharmacol. 8, 339-345.
    Pubmed CrossRef
  36. Lee, E., Jung, D.Y., Kim, J.H., Patel, P.R., Hu, X., Lee, Y., Azuma, Y., Wang, H.F., Tsitsilianos, N., and Shafiq, U. (2015). Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance. FASEB J. 29, 3182-3192.
    Pubmed KoreaMed CrossRef
  37. Lee, J.E., Kim, Y., Kim, K.H., Lee, D.Y., and Lee, Y. (2016). Contribution of Drosophila TRPA1 to metabolism. PLoS One. 11, e0152935.
    Pubmed KoreaMed CrossRef
  38. Lee, Y. (2013). Contribution of Drosophila TRPA1-expressing neurons to circadian locomotor activity patterns. PLoS One. 8, e85189.
    Pubmed KoreaMed CrossRef
  39. Leibiger, I.B., Leibiger, B., and Berggren, P.O. (2002). Insulin feedback action on pancreatic β-cell function. FEBS Lett. 532, 1-6.
    Pubmed CrossRef
  40. Liedtke, W., Choe, Y., Martí-Renom, M.A., Bell, A.M., Denis, C.S., Hudspeth, A., Friedman, J.M., and Heller, S. (2000). Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell. 103, 525-535.
    Pubmed KoreaMed CrossRef
  41. Liu, D., Zhu, Z., and Tepel, M. (2008). The role of transient receptor potential channels in metabolic syndrome. Hypertens Res. 31, 1989-1995.
    Pubmed CrossRef
  42. Liu, H., Dear, A.E., Knudsen, L.B., and Simpson, R.W. (2009). A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol. 201, 59-66.
    Pubmed CrossRef
  43. Liu, M., Huang, W., Wu, D., and Priestley, J.V. (2006). TRPV1, but not P2X3, requires cholesterol for its function and membrane expression in rat nociceptors. Eur J Neurosci. 24, 1-6.
    Pubmed CrossRef
  44. Liu, P., Shah, B.P., Croasdell, S., and Gilbertson, T.A. (2011). Transient receptor potential channel type M5 is essential for fat taste. J Neurosci. 31, 8634-8642.
    Pubmed KoreaMed CrossRef
  45. Lyall, V., Heck, G.L., Vinnikova, A.K., Ghosh, S., Phan, T.H.T., Alam, R.I., Russell, O.F., Malik, S.A., Bigbee, J.W., and DeSimone, J.A. (2004). The mammalian amiloride-insensitive non-specific salt taste receptor is a vanilloid receptor-1 variant. J Physiol. 558, 147-159.
    Pubmed KoreaMed CrossRef
  46. Macpherson, L.J., Dubin, A.E., Evans, M.J., Marr, F., Schultz, P.G., Cravatt, B.F., and Patapoutian, A. (2007). Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature. 445, 541-545.
    Pubmed CrossRef
  47. Marshall, N.J., Liang, L., Bodkin, J., Dessapt-Baradez, C., Nandi, M., Collot-Teixeira, S., Smillie, S.J., Lalgi, K., Fernandes, E.S., and Gnudi, L. (2012). A role for TRPV1 in influencing the onset of cardiovascular disease in obesity. Hypertension. 61, 246-252.
    Pubmed CrossRef
  48. Masuda, Y., Haramizu, S., Oki, K., Ohnuki, K., Watanabe, T., Yazawa, S., Kawada, T., Hashizume, S., and Fushiki, T. (2003). Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog. J Appl Physiol. 95, 2408-2415.
    Pubmed CrossRef
  49. Matsuura, H., Sokabe, T., Kohno, K., Tominaga, M., and Kadowaki, T. (2009). Evolutionary conservation and changes in insect TRP channels. BMC Evol Biol. 9, 228.
    Pubmed KoreaMed CrossRef
  50. Monet, M., Gkika, D., Lehen’kyi, V., Pourtier, A., Abeele, F.V., Bidaux, G., Juvin, V., Rassendren, F., Humez, S., and Prevarsakaya, N. (2009). Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation. Biochim Biophys Acta. 1793, 528-539.
    Pubmed CrossRef
  51. Montell, C. (2005). The TRP superfamily of cation channels. Sci STKE. 2005, re3.
    Pubmed CrossRef
  52. Montell, C. and Rubin, G.M. (1989). Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron. 2, 1313-1323.
    Pubmed CrossRef
  53. Moqrich, A., Hwang, S.W., Earley, T.J., Petrus, M.J., Murray, A.N., Spencer, K.S., Andahazy, M., Story, G.M., and Patapoutian, A. (2005). Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science. 307, 1468-1472.
    Pubmed CrossRef
  54. Moran, M.M., McAlexander, M.A., Bíró, T., and Szallasi, A. (2011). Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov. 10, 601.
    Pubmed CrossRef
  55. Morita, H., Honda, A., Inoue, R., Ito, Y., Abe, K., Nelson, M.T., and Brayden, J.E. (2007). Membrane stretch-induced activation of a TRPM4-like nonselective cation channel in cerebral artery myocytes. J Pharmacol. 103, 417-426.
    Pubmed CrossRef
  56. Motter, A.L. and Ahern, G.P. (2008). TRPV1-null mice are protected from diet-induced obesity. FEBS Lett. 582, 2257-2262.
    Pubmed KoreaMed CrossRef
  57. Nijenhuis, T., Hoenderop, J.G., and Bindels, R.J. (2005). TRPV5 and TRPV6 in Ca2+ (re)absorption: regulating Ca2+ entry at the gate. Pflügers Arch. 451, 181-192.
    Pubmed CrossRef
  58. Nilius, B. and Owsianik, G. (2011). The transient receptor potential family of ion channels. Genome Biol. 12, 218.
    Pubmed KoreaMed CrossRef
  59. Nilius, B., Owsianik, G., Voets, T., and Peters, J.A. (2007). Transient receptor potential cation channels in disease. Physiol Rev. 87, 165-217.
    Pubmed CrossRef
  60. Nilius, B. and Szallasi, A. (2014). Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol Rev. 66, 676-814.
    Pubmed CrossRef
  61. Nozawa, K., Kawabata-Shoda, E., Doihara, H., Kojima, R., Okada, H., Mochizuki, S., Sano, Y., Inamura, K., Matsushime, H., and Koizumi, T. (2009). TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proc Natl Acad Sci. 106, 3408-3413.
    Pubmed KoreaMed CrossRef
  62. Palmer, R.K., Atwal, K., Bakaj, I., Carlucci-Derbyshire, S., Buber, M.T., Cerne, R., Cortés, R.Y., Devantier, H.R., Jorgensen, V., and Pawlyk, A. (2010). Triphenylphosphine oxide is a potent and selective inhibitor of the transient receptor potential melastatin-5 ion channel. Assay Drug Dev Technol. 8, 703-713.
    Pubmed CrossRef
  63. Palmer, R.K. and Lunn, C.A. (2013). TRP channels as targets for therapeutic intervention in obesity: focus on TRPV1 and TRPM5. Curr Top Med Chem. 13, 247-257.
    Pubmed CrossRef
  64. Parks, D.J., Parsons, W.H., Colburn, R.W., Meegalla, S.K., Ballentine, S.K., Illig, C.R., Qin, N., Liu, Y., Hutchinson, T.L., and Lubin, M.L. (2010). Design and optimization of benzimidazole-containing transient receptor potential melastatin 8 (TRPM8) antagonists. J Med Chem. 54, 233-247.
    Pubmed CrossRef
  65. Peier, A.M., Moqrich, A., Hergarden, A.C., Reeve, A.J., Andersson, D.A., Story, G.M., Earley, T.J., Dragoni, I., McIntyre, P., and Bevan, S. (2002). A TRP channel that senses cold stimuli and menthol. Cell. 108, 705-715.
    Pubmed CrossRef
  66. Perraud, A.L., Takanishi, C.L., Shen, B., Kang, S., Smith, M.K., Schmitz, C., Knowles, H.M., Ferraris, D., Li, W., and Zhang, J. (2005). Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. J Biol Chem. 280, 6138-6148.
    Pubmed CrossRef
  67. Qin, N., Neeper, M.P., Liu, Y., Hutchinson, T.L., Lubin, M.L., and Flores, C.M. (2008). TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci. 28, 6231-6238.
    Pubmed KoreaMed CrossRef
  68. Rabini, R.A., Galassi, R., Fumelli, P., Dousset, N., Solera, M.L., Valdiguie, P., Curatola, G., Ferretti, G., Taus, M., and Mazzanti, L. (1994). Reduced Na(+)-K(+)-ATPase activity and plasma lysophosphatidylcholine concentrations in diabetic patients. Diabetes. 43, 915-919.
    Pubmed CrossRef
  69. Ramsey, I.S., Delling, M., and Clapham, D.E. (2006). An introduction to TRP channels. Annu Rev Physiol. 68, 619-647.
    Pubmed CrossRef
  70. Razavi, R., Chan, Y., Afifiyan, F.N., Liu, X.J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., and Santamaria, P. (2006). TRPV1+ sensory neurons control β cell stress and islet inflammation in autoimmune diabetes. Cell. 127, 1123-1135.
    Pubmed CrossRef
  71. Riera, C.E., Huising, M.O., Follett, P., Leblanc, M., Halloran, J., Van Andel, R., de Magalhaes Filho, C.D., Merkwirth, C., and Dillin, A. (2014). TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell. 157, 1023-1036.
    Pubmed CrossRef
  72. Rossato, M., Granzotto, M., Macchi, V., Porzionato, A., Petrelli, L., Calcagno, A., Vencato, J., De Stefani, D., Silvestrin, V., and Rizzuto, R. (2014). Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol. 383, 137-146.
    Pubmed CrossRef
  73. Saito, M. and Yoneshiro, T. (2013). Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans. Curr Opin Lipidol. 24, 71-77.
    Pubmed CrossRef
  74. Seabrook, G.R., Sutton, K.G., Jarolimek, W., Hollingworth, G.J., Teague, S., Webb, J., Clark, N., Boyce, S., Kerby, J., and Ali, Z. (2002). Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. J Pharmacol Exp Ther. 303, 1052-1060.
    Pubmed CrossRef
  75. Shen, D., Wang, X., Li, X., Zhang, X., Yao, Z., Dibble, S., Dong, X.P., Yu, T., Lieberman, A.P., and Showalter, H.D. (2012). Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nature Commun. 3, 731.
    Pubmed KoreaMed CrossRef
  76. Smeets, A.J. and Westerterp-Plantenga, M.S. (2009). The acute effects of a lunch containing capsaicin on energy and substrate utilisation, hormones, and satiety. Euro J Nutr. 48, 229-234.
    Pubmed KoreaMed CrossRef
  77. Sohn, J.W., Elmquist, J.K., and Williams, K.W. (2013). Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 36, 504-512.
    Pubmed KoreaMed CrossRef
  78. Sprous, D. and Palmer, R.K. (2010). The T1R2/T1R3 sweet receptor and TRPM5 ion channel: taste targets with therapeutic potential. Prog Mol Biol Transl Sci. 91, 151-208.
    Pubmed CrossRef
  79. Suzuki, M., Mizuno, A., Kodaira, K., and Imai, M. (2003). Impaired pressure sensation in mice lacking TRPV4. J Biol Chem. 278, 22664-22668.
    Pubmed CrossRef
  80. Svobodova, B. and Groschner, K. (2016). Mechanisms of lipid regulation and lipid gating in TRPC channels. Cell Calcium. 59, 271-279.
    Pubmed CrossRef
  81. Takezawa, R., Cheng, H., Beck, A., Ishikawa, J., Launay, P., Kubota, H., Kinet, J.P., Fleig, A., Yamada, T., and Penner, R. (2006). A pyrazole derivative potently inhibits lymphocyte Ca2+ influx and cytokine production by facilitating TRPM4 channel activity. Mol Pharmacol. 69, 1413-1420.
    Pubmed CrossRef
  82. Tani, Y., Fujioka, T., Sumioka, M., Furuichi, Y., Hamada, H., and Watanabe, T. (2004). Effects of capsinoid on serum and liver lipids in hyperlipidemic rats. J Nutr Sci Vitaminol. 50, 351-355.
    Pubmed CrossRef
  83. Tiede, S., Cantz, M., Spranger, J., and Braulke, T. (2006). Missense mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTA) in a patient with mucolipidosis II induces changes in the size and cellular distribution of GNPTG. Hum Mutat. 27, 830-831.
    Pubmed CrossRef
  84. Tiede, S., Muschol, N., Reutter, G., Cantz, M., Ullrich, K., and Braulke, T. (2005). Missense mutations in N-acetylglucosamine-1-phosphotransferase α/β subunit gene in a patient with mucolipidosis III and a mild clinical phenotype. Am J Med Genet A. 137, 235-240.
    Pubmed CrossRef
  85. Togashi, K., Hara, Y., Tominaga, T., Higashi, T., Konishi, Y., Mori, Y., and Tominaga, M. (2006). TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. EMBO J. 25, 1804-1815.
    Pubmed KoreaMed CrossRef
  86. Trevisani, M., Siemens, J., Materazzi, S., Bautista, D.M., Nassini, R., Campi, B., Imamachi, N., Andre, E., Patacchini, R., and Cottrell, G.S. (2007). 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci. 104, 13519-13524.
    Pubmed KoreaMed CrossRef
  87. Uchida, K., Dezaki, K., Yoneshiro, T., Watanabe, T., Yamazaki, J., Saito, M., Yada, T., Tominaga, M., and Iwasaki, Y. (2017). Involvement of thermosensitive TRP channels in energy metabolism. J Physiol Sci. 67, 549-560.
    Pubmed CrossRef
  88. Uchida, K. and Tominaga, M. (2011). The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion. Endocr J. 58, 1021-1028.
    Pubmed CrossRef
  89. Venkatachalam, K. and Montell, C. (2007). TRP channels. Annu Rev Biochem. 76, 387-417.
    Pubmed KoreaMed CrossRef
  90. Venkatachalam, K., Wong, C.O., and Montell, C. (2013). Feast or famine: role of TRPML in preventing cellular amino acid starvation. Autophagy. 9, 98-100.
    Pubmed KoreaMed CrossRef
  91. Walder, R.Y., Yang, B., Stokes, J.B., Kirby, P.A., Cao, X., Shi, P., Searby, C.C., Husted, R.F., and Sheffield, V.C. (2009). Mice defective in Trpm6 show embryonic mortality and neural tube defects. Hum Mol Genet. 18, 4367-4375.
    Pubmed KoreaMed CrossRef
  92. Wang, H. and Siemens, J. (2015). TRP ion channels in thermosensation, thermoregulation and metabolism. Temperature. 2, 178-187.
    Pubmed KoreaMed CrossRef
  93. Wang, X., Miyares, R.L., and Ahern, G.P. (2005). Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1. J Physiol. 564, 541-547.
    Pubmed KoreaMed CrossRef
  94. Wanner, S.P., Garami, A., and Romanovsky, A.A. (2011). Hyperactive when young, hypoactive and overweight when aged: connecting the dots in the story about locomotor activity, body mass, and aging in Trpv1 knockout mice. Aging (Albany NY). 3, 450-457.
    Pubmed KoreaMed CrossRef
  95. Whiting, S., Derbyshire, E., and Tiwari, B. (2014). Could capsaicinoids help to support weight management? A systematic review and meta-analysis of energy intake data. Appetite. 73, 183-188.
    Pubmed CrossRef
  96. Williams, K.W. and Elmquist, J.K. (2012). From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat Neurosci. 15, 1350.
    Pubmed KoreaMed CrossRef
  97. Wong, C.O., Li, R., Montell, C., and Venkatachalam, K. (2012). Drosophila TRPML is required for TORC1 activation. Curr Biol. 22, 1616-1621.
    Pubmed KoreaMed CrossRef
  98. Wu, X., Eder, P., Chang, B., and Molkentin, J.D. (2010). TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc Natl Acad Sci. 107, 7000-7005.
    Pubmed KoreaMed CrossRef
  99. Xiao, B., Dubin, A.E., Bursulaya, B., Viswanath, V., Jegla, T.J., and Patapoutian, A. (2008). Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels. J Neurosci. 28, 9640-9651.
    Pubmed KoreaMed CrossRef
  100. Xu, H., Blair, N.T., and Clapham, D.E. (2005). Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J Neurosci. 25, 8924-8937.
    Pubmed CrossRef
  101. Ye, L., Kleiner, S., Wu, J., Sah, R., Gupta, R.K., Banks, A.S., Cohen, P., Khandekar, M.J., Boström, P., and Mepani, R.J. (2012). TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell. 151, 96-110.
    Pubmed KoreaMed CrossRef
  102. Yoshioka, M., Lim, K., Kikuzato, S., Kiyonaga, A., Tanaka, H., Shindo, M., and Suzuki, M. (1995). Effects of red-pepper diet on the energy metabolism in men. J Nutr Sci Vitaminol. 41, 647-656.
    Pubmed CrossRef
  103. Yu, X., Yu, M., Liu, Y., and Yu, S. (2016). TRP channel functions in the gastrointestinal tract. Semin Immunopathol. 38, 385-396.
    Pubmed CrossRef
  104. Zhang, L.L., Yan Liu, D., Ma, L.Q., Luo, Z.D., Cao, T.B., Zhong, J., Yan, Z.C., Wang, L.J., Zhao, Z.G., and Zhu, S.J. (2007). Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res. 100, 1063-1070.
    Pubmed CrossRef
  105. Zhang, Z., Zhang, W., Jung, D.Y., Ko, H.J., Lee, Y., Friedline, R.H., Lee, E., Jun, J., Ma, Z., and Kim, F. (2012). TRPM2 Ca2+ channel regulates energy balance and glucose metabolism. Am J Physiol Endocrinol Metab. 302, E807-E816.
    Pubmed KoreaMed CrossRef
  106. Zhu, Z., Luo, Z., Ma, S., and Liu, D. (2011). TRP channels and their implications in metabolic diseases. Pflügers Arch. 461, 211-223.
    Pubmed CrossRef
  107. Zsombok, A. and Derbenev, A.V. (2016). TRP channels as therapeutic targets in diabetes and obesity. Pharmaceuticals. 9, 50.
    Pubmed KoreaMed CrossRef

Article

Minireview

Mol. Cells 2019; 42(8): 569-578

Published online August 31, 2019 https://doi.org/10.14348/molcells.2019.0007

Copyright © The Korean Society for Molecular and Cellular Biology.

Transient Receptor Potential Channels and Metabolism

Subash Dhakal and Youngseok Lee*

Department of Bio and Fermentation Convergence Technology, Kookmin University, BK21 PLUS Project, Seoul 02707, Korea

Correspondence to:ylee@kookmin.ac.kr

Received: January 20, 2019; Revised: July 27, 2019; Accepted: August 13, 2019

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/.

Abstract

Transient receptor potential (TRP) channels are nonselective cationic channels, conserved among flies to humans. Most TRP channels have well known functions in chemosensation, thermosensation, and mechanosensation. In addition to being sensing environmental changes, many TRP channels are also internal sensors that help maintain homeostasis. Recent improvements to analytical methods for genomics and metabolomics allow us to investigate these channels in both mutant animals and humans. In this review, we discuss three aspects of TRP channels, which are their role in metabolism, their functional characteristics, and their role in metabolic syndrome. First, we introduce each TRP channel superfamily and their particular roles in metabolism. Second, we provide evidence for which metabolites TRP channels affect, such as lipids or glucose. Third, we discuss correlations between TRP channels and obesity, diabetes, and mucolipidosis. The cellular metabolism of TRP channels gives us possible therapeutic approaches for an effective prophylaxis of metabolic syndromes.

Keywords: metabolic diseases, metabolism, transient receptor potential channel

INTRODUCTION

Transient receptor potential (TRP) channels are highly conserved transmembrane protein channels present in organisms, ranging from worms to mammals (Venkatachalam and Montell, 2007). These cationic channels were first characterized in the vinegar fly, Drosophila melanogaster. While a visual mechanism using forward genetic screening was being studied, a mutant fly showed a transient response to constant light instead of the continuous electroretinogram response recorded in the wild type (Cosens and Manning, 1969). Therefore, the mutant was named as transient receptor potential (trp). In the beginning, researchers had spent two decades discovering the trp locus with the germ-line transformation of the genomic region (Montell and Rubin, 1989). Using a detailed structural permeation property analysis in light-induced current, the TRP channel was confirmed as a six transmembrane domain protein, bearing a structural resemblance to a calcium-permeable cation channel (Montell and Rubin, 1989). This channel system shows structural resemblance with voltage-gated cation channels but largely different in composition of the positively charged amino acid residues which determines voltage sensing (Morita et al., 2007). So far, about 100 trp genes have been reported in many animals (Nilius et al., 2007). TRP channels are subdivided into two groups and seven subfamilies: Group 1 includes TRPC (canonical, C1–C7), TRPV (vanilloid, V1–V6), TRPM (melastatin, M1–M8), TRPA (ankyrin, A1), and TRPN (NOMP-like). Group 2 includes TRPP (polycystin, P1–P5) and TRPML (mucolipin, ML1–ML3) (Nilius and Owsianik, 2011).

The ancient TRP channels which are present in protists, chlorophyte algae, choanoflagellates, yeasts, and fungi are primarily involved in chemosensory, thermosensory, or mechanosensory functions (Matsuura et al., 2009; Wu et al., 2010). Many of these functions are remarkably conserved and can be found in various groups, including protists, worms, flies, and humans (Montell, 2005). TRP channels are involved in diverse physiological functions, ranging from sensation (pheromone signaling, visual, auditory, and taste transduction, nociception, and temperature sensation) to motility (muscle contraction and vaso-motor control). Furthermore, TRP channels are the key participants in the regulation of gut motility, mineral absorption, blood circulation, bladder and airway hypersensitivities, body fluid balance, cell growth, and survival (Nilius et al., 2007; Uchida et al., 2017).

Metabolism and glucose homeostasis are tightly regulated processes (Williams and Elmquist, 2012). The central nervous system (CNS) incorporates both central and peripheral signals for the coordinated control and modulation of food consumption, glucose homeostasis, and energy expenditure. However, in vivo study of physiological roles of TRP channels expressed in the CNS is still insufficient. Around 30 TRP channels are documented to be expressed in the digestive system. They are involved in taste, gastrointestinal movement, absorption, secretion, and maintenance of mucosal homeostasis (Holzer, 2011; Lee et al., 2016). Interestingly, involvement of various hormones and neurotransmitters alter the activity of channel system that controls the neuronal functions in the central regulation of metabolism (Brownstein, 1977). Combined studies using mouse genetics, together with neuroanatomical methods and electrophysiological examination, have provided new findings about the roles of various ion channels that modulate neurons associated with metabolism and related disorders (Sohn et al., 2013).

TRP channels are present in various metabolically important tissues. They are widely expressed in the pancreatic cells, liver, gastrointestinal tract (Yu et al., 2016), skeletal muscle, kidney, adipose tissue, heart, vasculature, and nervous system (Zhu et al., 2011). Although TRP channels and their ligands are potential targets to treat obesity and diabetes in the field of metabolic diseases (Nilius and Szallasi, 2014), their roles in many metabolic processes are still controversial and being studied. Here we discuss the role of TRP channels in metabolism and suggest numerous avenues for future study.

TRP CHANNELS IN METABOLISM

Members of the TRP channels play important physiological roles and can be observed in cells in different metabolic states. They work as gatekeepers for the trans-cellular transport of several cations, including Ca2+ and Mg2+, but their biological roles are diverse (Table 1) (Nilius and Owsianik, 2011).

TRPA

TRPA1 is a receptor for a broad range of environmental oxidants and irritants and has a central role in pain and other preclinical conditions (Julius, 2013). It is directly activated by cinnamaldehyde, allyl isothiocyanate (AITC), allicin, formalin, and icilin (Bessac and Jordt, 2008; Macpherson et al., 2007; Trevisani et al., 2007). In association with cinnamaldehyde, TRPA1 drives insulin and ghrelin secretion, enhances insulin sensitivity in the CNS and reduces the deposition of fat in the liver. Supplementing AITC with a high-fat diet causes less weight gain compared with high-fat diet alone in mouse model (Ahn et al., 2014). Drosophila TRPA1 (dTRPA1) is highly expressed in the posterior dorsal ganglion of the fly brain and the axon bundles of the place are sent to the sub-esophageal zone, which is a primary center to regulate feeding (Lee, 2013). This indicates possible direct control in metabolism of dTRPA1 in brain. Non-targeted metabolomic profiling revealed that mutations in dTRPA1 had a direct effect on the free fatty-acid metabolism and methionine salvage pathway. Furthermore, trehalose is a sugar associated with cellular processes for heat protection. This process is slightly upregulated in a trpA1 mutant background (Lee et al., 2016). TRPA1 has a role in enteroendocrine L-cells of the intestine. The gut hormone, glucagon-like peptide 1 (GLP-1) has a crucial role in glucose metabolism. It acts via changing insulin secretion on the gut–brain axis. Administration of TRPA1 into the duodenum resulted in GLP-1 secretion from these cells. So higher levels of GLP-1 can be an alternative hallmark in antidiabetic therapy (Smeets and Westerterp-Plantenga, 2009). TRPA1 is also expressed in enterochromaffin cells that contain cholecystokinin (CCK). The activation of TRPA1 causes satiety in mice via CCK secretion (Nozawa et al., 2009). Methyl syringate, one of the TRPA1 agonists, decreases food ingestion and gastric emptying in mouse models (Kim et al., 2013). However, TRPA1 is also expressed in the tongue of mammals and insects (Kim et al., 2010; Xiao et al., 2008). It is possible that TRPA1 agonists can directly activate taste receptor cells to reduce ingestion. So it is combinatory effect in pheripheral as well as internal sensors.

TRPV

The TRPV channel subfamily has six members categorized into two groups: TRPV1–V4 and TRPV5–V6. TRPV1–V4 consists of the thermo-TRPs that are triggered by specific temperature threshold. Although TRPVs that are thermosensitive seem to function in sensing temperature changes, these channels are also present in tissues where dramatic temperature swings are prevented by thermoregulatory homeostasis. Thus, temperature may perform a permissive rather than essential role in controlling the activity of these TRPs (Lyall et al., 2004; Moqrich et al., 2005). TRPV5 and TRPV6 have a role to reabsorb Ca2+ from the kidney and intestine, respectively (Nijenhuis et al., 2005).

TRPV1 has a role in potential sensory nerves that innervate into pancreatic islets and adipose tissues for insulin production. These channels are expressed in several neuronal (from olfactory, basal ganglion to cerebellum) and non-neuronal (buccal cavity, intestine, stomach, liver, and pancreas) cells (Nilius and Szallasi, 2014; Seabrook et al., 2002). TRPV1 channel is activated by temperature threshold around 42°C, and hot pepper ingredient, capsaicin. Ingestion of capsaicin, the well-known TRPV1 agonist, prevents diet-induced obesity in mouse models (Kang et al., 2010). Adipose tissue expresses TRPV1, but the tissue isolated from obese animals including humans displayed reduced expression level of TRPV1 (Chu et al., 2003; Zhang et al., 2012). TRPV1 knock-out (KO) mice developed age-associated obesity and hypo-metabolism (Wang and Siemens, 2015). However, recent findings have indicated that the prevention of obesity as beneficial effects seem to be minute and would in all probability require daily long-term intake of capsaicin (Saito and Yoneshiro, 2013; Whiting et al., 2014). While consuming a standard chow diet, TRPV1 KO mice showed normal insulin sensitivity, with comparable glucose metabolism rates to wild-type mice (Lee et al., 2015). Interestingly, TRPV1 KO mice were also protected from obesity caused by diet and exhibited an increased longevity, which correlated with the prolongation of a juvenile metabolic profile (Motter and Ahern, 2008).

In addition, TRPV1 is found to participate in multifaceted metabolic functions in various other tissues, including the adipose tissue, hypothalamus, and the gastrointestinal tract (Baboota et al., 2014). However, the exact roles underlying their protective functions in these tissues remain obscure. Relying on the metabolic state and cell type, TRPV1 has been a positive inducing factor for metabolic homeostasis. Activation of TRPV3 triggers inhibition of the phosphorylation of insulin receptor substrate-1 (IRS-1) and suppression of PPAR-γ, thus preventing lipid accumulation and adipogenesis (Bang et al., 2010; 2011; Ye et al., 2012). In brown adipose tissue (BAT), activation of TRPV4 negatively operates oxidative metabolism (Ye et al., 2012). The loss of TRPV4 results in a rise of oxidative potential in skeletal muscle by a compensatory regulatory mechanism (Kusudo et al., 2011). Interestingly, creating TRPV4 KO mice or antagonizing TRPV4 by pharmacologic blockade with glibenclamide elevates thermogenesis in adipose tissue and protects against adipose inflammation, diet-mediated obesity, and insulin resistance. TRPV4 in adipose tissue boosts pro-inflammatory cytokines (Bang et al., 2012; Ye et al., 2012).

TRPM

The TRPM subfamily is composed of eight members, which are categorized into three groups based on their structural homology: TRPM1/3, TRPM4/5, and TRPM6/7. TRPM2 and TRPM8 have relatively low sequence homology with the others and therefore they are not included in the group. TRPM2, TRPM6, and TRPM7 are distinctive among other TRPM channels because they have active enzyme domains in their C-termini merged to their transmembrane domains (Moran et al., 2011; Walder et al., 2009). TRPM2, TRPM3, TRPM4, and TRPM5 have been distinguished to contribute in the regulation of metabolism (Zhu et al., 2011).

TRPM2, TRPM3, TRPM4, and TRPM5 are present in rodent insulinoma cells and mouse islets. TRPM2, TRPM4, and TRPM5 have a role in the regulation of insulin secretion. TRPM2 and TRPM4 channels are present in insulin-producing pancreatic β-cells, and expression of dominant negative forms of TRPM4 and TRPM2 small interfering RNAs (siRNAs) decreases insulin secretion from the β-cells (Cheng et al., 2007; Grand et al., 2008; Kraft et al., 2006; Togashi et al., 2006). TRPM5 is also important for Ca2+-activated cation channels in β-cells and GLP-1 secreting L-cells. Much like the TRPV1, the TRPM8 channel has a role in adipocytes (Fernandes et al., 2012; Parks et al., 2010; Rossato et al., 2014). Menthol is a known TRPM8 agonist which induces hyperactivity and suppresses diet-induced weight gain (Jiang et al., 2017; Peier et al., 2002). Menthol amplifies uncoupling protein 1 (UCP-1) expression in BAT in a dose-dependent way. However, this effect disappears in TRPM8 KO mice. Mice can be prevented from diet-induced obesity through prolonged dietary menthol supplements. In humans, TRPM8 activation can induce the browning of white adipose tissue (WAT browning), possibly by accelerating energy consumption (Rossato et al., 2014).

TRPM2 KO mice have deficits in insulin production under both high-fat or normal diet (Uchida and Tominaga, 2011). TRPM2 is broadly expressed in organs including the heart, brain, kidney and the immune system. It also functions as an oxidative stress sensor (Jang et al., 2014; Perraud et al., 2005). Moreover, TRPM2, TRPM4, and TRPM5 are controlled via CNS and have roles in neuronal activation, neurodegeneration, and cell death (Ramsey et al., 2006).

FUNCTIONAL CHARACTERISTICS OF TRP CHANNELS

Lipid metabolism

TRP channels have been shown to be key regulatory proteins involved in the process of lipid metabolism and energy homeostasis (Zhu et al., 2011). TRPV1 activation by capsaicin induces decreased triglyceride amounts in 3T3-L1 pre-adipocytes during adipogenesis. Similarly, capsaicin reduces dietary high-fat-induced hypertriglyceridemia in rats by exhibiting higher lipoprotein lipase movement in adipose tissues (Tani et al., 2004). Depending on the membrane lipid content, the localization, and function of TRP channel can be controlled. When methyl-β-cyclodextrin was treated in rat arteries as the cholesterol acceptor, membrane cholesterol is reduced, and trpC1 expression level is decreased (Bergdahl et al., 2003). Similarly, cholesterol depletion in adult rat DRGs reduces TRPV1 levels in membrane, which induces decrease of TRPV1 currents mediated by proton or capsaicin (Liu et al., 2006). Furthermore, lysophosphatidylcholine (LPC) derived from phosphatidylcholine in cell membrane activates TRPC6 in cultured human corporal smooth muscle cells. LPC is one of major phospholipids of oxidized low density lipoprotein (LDL), which is an active pro-inflammatory lipid in pathological conditions (Rabini et al., 1994). Moreover, LPC and lysophosphatidylinositol (LPI) are able to induce TRPV2 activation. This activation mediated by Gq/Go and phosphatidylinositol-3,4 kinase (PI3,4K) signaling, seems to be mostly attributable to TRPV2 localization to the plasma membrane. It is highly dependent on the lysophospholipid head group and the length of the side-chain. In prostate cancer, metastasis of the cells is increased by TRPV2 activation by LPC and LPI (Monet et al., 2009). This may suggest a pathological role of TRPV2. Furthermore, 7-ketocholesterol, as a component of oxidized LDL, induces TRPC1 translocation to lipid rafts, activation of the channel, and increased calcium influx (Berthier, 2004).

Some studies have highlighted differences in intracellular Ca2+ concentration among normal and insulin-resistant cardiomyocytes by the application of bipolar lipids. Exogenous polyunsaturated fatty acids (PUFAs) bypass endogenous synthesis of PUFAs by eliciting TRPV1-dependent Ca2+ inward currents in sensory neurons (Kahn-Kirby et al., 2004; Lanner et al., 2008). Both cholesterol and sphingolipids as raft-enriched lipids may have effects on TRP channel activity, either via direct protein-lipid interactions or by affecting the physical properties of the lipid bilayer (Dart, 2010). Lipid signaling and lipotoxicity are strongly connected with oxidative metabolism. As a result, lipid agonists or modulators of TRPC channels are subject to oxidative modification (Svobodova and Groschner, 2016).

Glucose metabolism

Hyperglycaemia significantly increases TRPC6 in platelets, whereas expression of other TRPC members remain the same (Liu et al., 2009). GLUT4 is a glucose transporter protein, which is highly expressed in mammalian adipose tissues and skeletal muscles (Huang and Czech, 2007). Unlike other cohorts of glucose transporters, GLUT4 responds efficiently to insulin. A variety of genetically engineered mouse models have been used to demonstrate the role of GLUT4 in maintaining whole body metabolism, including glucose homeostasis in muscles and energy sensors in adipocytes. However, GLUT4 KO mice show normal fat mass and adipocyte size, and normal glucose uptake in adipose tissues. GLUT4 is an energy sensor rather than a main regulator of glucose homeostasis in adipocytes (Yoshioka et al., 1995). Interestingly, TRPV1 KO mice showed longer life spans, with juvenile metabolic phenotypes, when their diet was supplemented with capsaicin, suggesting TRPV1 may cause diet-induced obesity in mice (Riera et al., 2014). In contrast, TRPM8 activation via diet supplements in mice was protective against diet-induced obesity (Rossato et al., 2014).

METABOLIC SYNDROME

TRP channels are widely present in the tissues including adipocytes, endothelial cells and vascular smooth muscles. So the deficits of TRP channels are highly related to numerous diseases and specifically related with the progression of varied cardiovascular diseases (Nilius et al., 2007). This explains their widespread functions. However, because they are widely distributed, disturbance in or alterations in expression of TRP channels may induce the development of metabolic syndrome (Table 2). Multiple channels such as TRPV1, TRPC3, TRPC6, and TRPC7 are activated essentially by diacylglycerol, whereas other TRPCs such as TRPC4, TRPC5, and TRPC6 are mainly activated after exhaustion of intracellular sarcoendoplasmic stores (Nilius et al., 2007). TRP channels may be directly affected by the agonists that were involved in the pathology of metabolic syndrome. For instance, angiotensin receptors are activated by angiotensin II. Series of ligand dependent activation cascade finally lead to the production of inositol triphosphate and diacylglycerol from phosphoinositide. These are the keys to open TRP channels, as elevation of diacylglycerol and depletion of inositol trisphosphate stores activate TRP channels (Bottari et al., 1993). The hetero-multimeric composition and expression of TRP channels maintain balance in the intracellular calcium homeostasis via transmembrane calcium influx. These functional alterations may develop metabolic syndromes (Liu et al., 2008).

Obesity

Obesity is the abnormal increase in body weight, as a sign of many of metabolic syndromes (Grundy, 2004). The TRPV1 channel is a key regulator of pre-adipocytes, appetite regulation, fat distribution, and obesity-induced chronic inflammatory responses. Both endogenous agonists (N-arachidonoyl dopamine and anandamide) and exogenous agonists (capsaicin and resiniferatoxin) may influence TRPV1 channel activity (Kumar et al., 2013). Application of capsaicin prevents adipogenesis and obesity in both mice and humans. Capsaicin increases intracellular calcium in pre-adipocytes but not in mature adipocytes, which is highly dependent on TRPV1 expression between pre-adipocytes and mature adipocytes (Xu et al., 2005; Zhang et al., 2007). However, when mice were fed on a high-fat diet, weight gain did not differ between TRPV1 KO and wild-type mice (Marshall et al., 2012). Moreover, ingestion of capsaicin with a high-fat diet did not block obesity in TRPV1 KO mice, although it affected obesity in wild-type (Zhang et al., 2007). This finding may be explained by another study that showed the phenotype of TRPV1 KO mice is dependent on age and environmental variables that have direct impact on thermoregulation (Wanner et al., 2011).

TRPV1 is expressed in visceral adipose tissues expressed in visceral as well as pre-adipocytes. When mice is fed with high sugar (high diet food) supplemented with TRPV1 agonist mono-acyl glycerol, it prevents white fat accumulation, activating mitochondrial UPC1 in BAT. Comparing obese male mice with their lean counterparts, the level of TRPV1 is alleviated in visceral tissues. Moreover, ingestion of capsaicin with a high fat diet did not block obesity in TRPV1 KO mice, although it affected obesity in wild type (Zhang et al., 2007). This activation of TRPV1 leads to PPAR-γ activation, nuclear factor NF-kB inactivation, the secretion of pro-inflammatory mediators by macrophage activation, and inhibition of obesity-associated macrophage migration. The obesity induced chronic inflammatory responses have major role in the developmental process of atherosclerosis and type II diabetes mellitus (T2DM) (Masuda et al., 2003). Endogenous TRPV1 agonist, N-oleoylethanolamide activates vagal sensory afferent neurons that regulate calorie intake and appetite. This phenomenon is investigated only in wild type mice, because only wild type mice showed decreased food consumption, suggesting that TRPV1 activation may control appetite (Wang et al., 2005).

Some TRPV members (V1–V4) have been proven to play pivotal roles in adipocytes. TRPV3 is highly expressed in adipocytes, and its activation prevents lipid buildup and adipogenesis (Cheung et al., 2015; Qin et al., 2008). In contrast, only TRPV1, TRPV2, and TRPV4 may have roles in 3T3-F442A pre-adipocytes. TRPV4 is highly expressed in this cell line, which confirms previous observation that exhibit TRPV4 expression in adipose tissue (Liedtke et al., 2000). Subcutaneous adipose tissue of TRPV4 KO mice showed higher UCP1 levels compared with control mice. Taken together, TRPVs results in having significant functions in adipocytes (Suzuki et al., 2003; Zsombok and Derbenev, 2016).

TRPM5 is a common downstream ion channel in type 2 taste receptor cells for GPCRs, which sense the basic tastes of sweet, umami, and bitter (Sprous and Palmer, 2010). Genetic changes in TRPM5 completely impaired the ability of mice to detect not only various tastes but also fat (Liu et al., 2011). Blocking TRPM5 in taste cells reduces appetite, so it can be a strategy to lose weight (Palmer and Lunn, 2013; Palmer et al., 2010; Sprous and Palmer, 2010). Quinine as a TRPM5 blocker induces weight loss in a mouse model (Cettour-Rose et al., 2013). Similarly, but inversely, levels of the fat hormone, adiponectin, are correlated with the amount of fat. Thus, overexpression of adiponectin increases energy expenditure and as a result, induces a lean body type. Blocking TRPC5 channels results in increase of plasma adiponectin, which can be beneficial to patients with metabolic disorders such as obesity and T2DM (Palmer and Lunn, 2013).

Diabetes

It is experimentally proven that several TRP channels have a practical role in the onset of diabetes mellitus (Liu et al., 2008). Among different TRPVs, TRPV1 has been found to control islets inflammation and insulin resistance by activating its associated pancreatic sensory neurons. Ablating TRPV1-associated pancreatic sensory neurons in diabetes-prone mice prevents developing diabetes and insulitis. This indicates that pathogenesis of type I diabetes mellitus is associated with TRPV1 activation (Razavi et al., 2006). Insulin signaling promotes mitochondrial oxidative capacity and ATP production. TRPA1 is abundant in rat pancreatic β cells (Colsoul et al., 2013). TRPA1 agonists such as mustard oil and 4-hydroxy-2-nonenal induce insulin secretion in pancreatic β cells. Furthermore, the TRPA1 antagonist including HC-030031 hinders insulin release induced by glucose increase. This provides the evidence that TRPA1 has a direct role to control insulin secretion (Leibiger et al., 2002).

TRPM2 activation induces calcium increase into pancreatic islets, and increases in the level of cyclic ADP-ribose. This results in regulating insulin secretion (Togashi et al., 2006). Reactive oxygen species (e.g., H2O2), glucose, and incretins are stimuli for the activation of TRPM2 (Uchida and Tominaga, 2011). TRPM2 KO mice are more sensitive to insulin because of increased glucose metabolism in their heart arising from the phosphorylation of elevated Akt and glycogen synthase kinase 3. TRPM2 KO mice also reduce inflammation in the adipose tissue and liver (Zhang et al., 2012). These evidences demonstrate that TRPM2 has a role in metabolism. Expression of TRPM2, TRPM4, and TRPM5 has been found in human islets of Langerhans, suggesting that they may regulate pancreatic function and insulin secretion (Colsoul et al., 2013; Takezawa et al., 2006).

Mucolipidosis

Lysosomal storage disorders are metabolic diseases characterized by a deficiency in the enzymes that are important for vesicular lipid, carbohydrate, and protein metabolism (Futerman and Van Meer, 2004). Four types of mucolipidosis have been identified based on their physiology and pathophysiology (David-Vizcarra et al., 2010). Mucolipidosis type IV (MLIV) is an autosomal recessive disorder, generated by mutations in transient receptor potential mucolipin 1 (TRPML1). In MLIV, TRPML1, a vesicular Ca2+ release channel, is non-functional. TRPML1 contributes to the fusion of amphisomes with lysosomes. Other types of mucolipidosis are caused by non-functional metabolic enzymes. These include mucolipidosis I (sialidosis), caused by aberrant sialidase, and mucolipidosis II and III, caused by mutated N-acetylglucosamine-1-phosphotransferase (Shen et al., 2012; Tiede et al., 2005; 2006). In Drosophila, a null mutation of trpml leads to pupal lethality, when the flies count to autophagy for nutrition. This pupal lethality is caused by reduced targets of rapamycin complex 1 (TORC1) signaling (Venkatachalam et al., 2013). This indicates that cellular amino acid starvation is one of the fundamental causes of toxicity in the TRPML deficiency. It raises the intriguing feasibility that neurological disorder in MLIV patients may therefore stem from amino acid deprivation. A high-protein diet can reduce pupal lethality and increase the amount of acidic vesicles. However, further inhibition of TORC1 activity by administering rapamycin worsens the trpml mutant phenotype. The severity of MLIV might be decreased with a high-protein diet (Wong et al., 2012).

CONCLUSION AND FUTURE PERSPECTIVES

TRP channels possess various metabolic functions which are thought to be key targets for different physiological processes. Glucose and lipid metabolism are the central pathways that maintain energy balance, thermal regulation, and control of the metabolome. Their dysfunction can cause metabolic diseases including obesity, diabetes, and mucolipidosis. The severity of these disorders can be diminished by the consumption of supplementary foods, such as capsaicin. However, the precise target of this supplementary dietary intake is not clearly understood because multiple tissues, such as adipose, pancreatic, and even CNS tissues may be modulated by these supplements. A systemic analysis would be required to reveal more of these mechanisms. Analysis of TRP channel mutated animals with regard to their metabolomes would help us to further understand TRP channel functions and related pathogenesis.

ACKNOWLEDGMENTS

S.D. was supported by the Global Scholarship Program for Foreign Graduate Students at Kookmin University in Korea. This work is supported by grants to Y.L. from the Basic Science Research Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education (NRF-2016R1D1A1B03931273 and NRF-2018R1A2B6004202).

. Receptors, activators and inhibitors of metabolic TRP channels.

Subfamily Locus Activators Inhibitors Functions References
TRPV
 TRPV1 Sensory neurons, brain, spinal cord, keratinocytes, pancreas, tongue, and bladder Cannabigerol, capsaicin, gingerol, lysophosphatidic acid, piperine, N-oleoyldopamine, palmitoylethanol-amide, and vanillotoxin Capsazepine, iodo-resinifera toxin, resolvin D2 thapsigargin, yohimbine, and BCTC Taste, salivary secretion, thermoregulation, intestinal ion and fluid secretion, gastric hormone release, and insulin release (Chu et al., 2003; Parks et al., 2010; Seabrook et al., 2002)
 TRPV2 Brain, spinal cord, sensory neurons, spleen, and GI-tract Camphor, incensole acetate, and lysophosphatidylcholine Tranilast Thermoregulation, insulin release, and glucose homeostasis (Qin et al., 2008)
 TRPV3 Brain, sensory neurons, and tongue Farnesyl pyrophosphate and menthol Isopentenyl pyrophosphate and resolvin D1 Taste, thermoregulation, and GI cancer (Bang et al., 2010; 2011; Moqrich et al., 2005)
 TRPV4 Brain, sensory neurons, kidney, heart, liver, spleen, and inner ear Citric acid, dimethylallyl pyrophosphate, apigenin, and 4α-phorbol 12, 13-de decanoate Resolvin D1, HC-067047, and RN-1734 Thermoregulation and pain (Bang et al., 2012; Suzuki et al., 2003)
TRPM
 TRPM2 Brain, pancreas liver, and heart ADP-ribose and cyclic ADP-ribose Clotrimazole, N-(p-amylcinnamoyl) anthranilic acid, and econazole Insulin secretion, diabetes, obesity, and CNS disorder (Kraft et al., 2006; Perraud et al., 2005)
 TRPM4 Pancreas, colon, bladder, and heart BTP2 9-phenanthrol and flufenamic acid Insulin release and bladder function (Grand et al., 2008; Takezawa et al., 2006)
 TRPM5 Brain, taste coil, pancreas, GI-tract, liver, and tongue Rutamarin and steviol glycosides NSAID drugs, nicotine, tri-phenyl phosphine oxide, and 2-APB Taste, gastric hormone secretion, and insulin release (Palmer et al., 2010)
 TRPM8 Sensory neurons, liver, stomach, prostate, and bladder Menthol, linalool, geraniol, hydroxycitronellal, WS-3, and frescolat MGA AMTB, BCTC, benzimidazoles, and 5-benzyloxytrypamine Taste and thermoregulation (Parks et al., 2010; Peier et al., 2002)
TRPA
 TRPA1 PNS, hair cells, and enter-endocrine cells 15-deoxy-Δ12, 14-PGJ2, 4-hydroxynonenal, 4-oxononenal, and methylglyoxal Camphor, menthol, resolvin D1, and resolvin D2 Taste, thermoregulation, and gastric hormone release (Macpherson et al., 2007; Xu et al., 2005)
 TRPML2 CNS, pancreas, and intracellular ion channels SF-51, ML-SA1, SID24801657, and SID24787221 Adenosine deaminase (ADA) Mucolipidosis (Shen et al., 2012)

. Involvement of TRP channels in each metabolic syndrome.

Subfamily Receptor Functions in obesity Functions in diabetes Functions in mucolipidosis References
TRPV TRPV1 Reduction in adipogenesis, appetite control, fat distribution, obesity-induced chronic inflammatory responses, and TRPV1 activation increase liver function Islets inflammation and insulin resistance, progression to T1DM - (Zhang et al., 2007)
TRPV2 TRPV2 activation negatively regulate BAT differentiation, reduce lipid accumulation, KO mice has more WAT with HFD induced obesity TRPV2 inhibition cause glucose induced insulin secretion - (Suzuki et al., 2003; Uchida et al., 2017)
TRPV3 Activation prevent lipid build-up and adipogenesis - - (Cheung et al., 2015)
TRPV4 Regulate UPC1 level in subcutaneous adipose tissue, negatively regulate oxidative metabolism, TRPV4 KO protect from adipose inflammation, diet-mediated obesity, and insulin resistance - - (Ye et al., 2012)
TRPML TRPML1 & TRPML2 - - trpml mutation causes pupal lethality, autophagy for nutrition, amino acid deprivation. Impairment in vascular carbohydrate, lipid and protein metabolism (Venkatachalam et al., 2013)
TRPM TRPM2 TRPM2 KO are resistant to diet induced obesity and inflammation Increase calcium level, induce insulin secretion from pancreatic islets, KO reduce inflammation in adipose tissue and liver - (Zhang et al., 2012)
TRPM3 - Regulate zinc level, trigger insulin secretion from beta-cells - (Colsoul et al., 2013)
TRPM4 - Glucagon synthesis from alpha cells, indirect role in insulin synthesis - (Colsoul et al., 2013)
TRPM5 Basic taste regulator, control appetite and obesity Increase insulin secretion and glucose tolerance, regulate plasma insulin level - (Palmer et al., 2010)
TRPM6 - Balance serum magnesium level, reduce possibility of T2DM - (Walder et al., 2009)
TRPM8 TRPM8 activation induces browning of WAT, induces UPC1 expression in BAT - - (Rossato et al., 2014)
TRPA TRPA1 Activation cause satiety and control obesity Activation induce insulin secretion from beta cells - (Macpherson et al., 2007)

References

  1. Ahn, J., Lee, H., Im, S.W., Jung, C.H., and Ha, T.Y. (2014). Allyl isothiocyanate ameliorates insulin resistance through the regulation of mitochondrial function. J Nutr Biochem. 25, 1026-1034.
    Pubmed CrossRef
  2. Baboota, R.K., Singh, D.P., Sarma, S.M., Kaur, J., Sandhir, R., Boparai, R.K., Kondepudi, K.K., and Bishnoi, M. (2014). Capsaicin induces “brite” phenotype in differentiating 3T3-L1 preadipocytes. PLoS One. 9, e103093.
    Pubmed KoreaMed CrossRef
  3. Bang, S., Yoo, S., Yang, T.J., Cho, H., and Hwang, S.W. (2010). Farnesyl pyrophosphate is a novel pain-producing molecule via specific activation of TRPV3. J Biol Chem. 285, 19362-19371.
    Pubmed KoreaMed CrossRef
  4. Bang, S., Yoo, S., Yang, T.J., Cho, H., and Hwang, S.W. (2011). Isopentenyl pyrophosphate is a novel antinociceptive substance that inhibits TRPV3 and TRPA1 ion channels. Pain. 152, 1156-1164.
    Pubmed CrossRef
  5. Bang, S., Yoo, S., Yang, T.J., Cho, H., and Hwang, S.W. (2012). Nociceptive and pro-inflammatory effects of dimethylallyl pyrophosphate via TRPV4 activation. Br J Pharmacol. 166, 1433-1443.
    Pubmed KoreaMed CrossRef
  6. Bergdahl, A., Gomez, M.F., Dreja, K., Xu, S.Z., Adner, M., Beech, D.J., Broman, J., Hellstrand, P., and Swärd, K. (2003). Cholesterol depletion impairs vascular reactivity to endothelin-1 by reducing store-operated Ca2+ entry dependent on TRPC1. Circ Res. 93, 839-847.
    Pubmed CrossRef
  7. Berthier, L. (2004). Time and length scales in supercooled liquids. Phys Rev E. 69, 020201.
    Pubmed CrossRef
  8. Bessac, B.F. and Jordt, S.E. (2008). Breathtaking TRP channels: TRPA1 and TRPV1 in airway chemosensation and reflex control. Physiology. 23, 360-370.
    Pubmed KoreaMed CrossRef
  9. Bottari, S.P., de Gasparo, M., Steckelings, U.M., and Levens, N.R. (1993). Angiotensin II receptor subtypes: characterization, signalling mechanisms, and possible physiological implications. Front Neuroendocrinol. 14, 123-171.
    Pubmed CrossRef
  10. Brownstein, M. (1977). Neurotransmitters and hypothalamic hormones in the central nervous system. Fed Proc. 36, 1960-1963.
    Pubmed
  11. Cettour-Rose, P., Bezençon, C., Darimont, C., le Coutre, J., and Damak, S. (2013). Quinine controls body weight gain without affecting food intake in male C57BL6 mice. BMC Physiol. 13, 5.
    Pubmed KoreaMed CrossRef
  12. Cheng, W., Yang, F., Takanishi, C.L., and Zheng, J. (2007). Thermosensitive TRPV channel subunits coassemble into heteromeric channels with intermediate conductance and gating properties. J Gen Physiol. 129, 191-207.
    Pubmed KoreaMed CrossRef
  13. Cheung, S.Y., Huang, Y., Kwan, H.Y., Chung, H.Y., and Yao, X. (2015). Activation of transient receptor potential vanilloid 3 channel suppresses adipogenesis. Endocrinology. 156, 2074-2086.
    Pubmed CrossRef
  14. Chu, C.J., Huang, S.M., De Petrocellis, L., Bisogno, T., Ewing, S.A., Miller, J.D., Zipkin, R.E., Daddario, N., Appendino, G., and Di Marzo, V. (2003). N-oleoyldopamine, a novel endogenous capsaicin-like lipid that produces hyperalgesia. J Biol Chem. 278, 13633-13639.
    Pubmed CrossRef
  15. Colsoul, B., Nilius, B., and Vennekens, R. (2013). Transient receptor potential (TRP) cation channels in diabetes. Curr Top Med Chem. 13, 258-269.
    Pubmed CrossRef
  16. Cosens, D. and Manning, A. (1969). Abnormal electroretinogram from a Drosophila mutant. Nature. 224, 285-287.
    Pubmed CrossRef
  17. Dart, C. (2010). Lipid microdomains and the regulation of ion channel function. J Physiol. 588, 3169-3178.
    Pubmed KoreaMed CrossRef
  18. David-Vizcarra, G., Briody, J., Ault, J., Fietz, M., Fletcher, J., Savarirayan, R., Wilson, M., McGill, J., Edwards, M., and Munns, C. (2010). The natural history and osteodystrophy of mucolipidosis types II and III. J Paediatr Child Health. 46, 316-322.
    Pubmed KoreaMed CrossRef
  19. Fernandes, E., Fernandes, M., and Keeble, J. (2012). The functions of TRPA1 and TRPV1: moving away from sensory nerves. Br J Pharmacol. 166, 510-521.
    Pubmed KoreaMed CrossRef
  20. Futerman, A.H. and Van Meer, G. (2004). The cell biology of lysosomal storage disorders. Nat Rev Mol Cell Biol. 5, 554-565.
    Pubmed CrossRef
  21. Grand, T., Demion, M., Norez, C., Mettey, Y., Launay, P., Becq, F., Bois, P., and Guinamard, R. (2008). 9-phenanthrol inhibits human TRPM4 but not TRPM5 cationic channels. Br J Pharmacol. 153, 1697-1705.
    Pubmed KoreaMed CrossRef
  22. Grundy, S.M. (2004). Obesity, metabolic syndrome, and cardiovascular disease. J Clin Endocrinol Metab. 89, 2595-2600.
    Pubmed CrossRef
  23. Holzer, P. (2011). Transient receptor potential (TRP) channels as drug targets for diseases of the digestive system. Pharmacol Ther. 131, 142-170.
    Pubmed KoreaMed CrossRef
  24. Huang, S. and Czech, M.P. (2007). The GLUT4 glucose transporter. Cell Metab. 5, 237-252.
    Pubmed CrossRef
  25. Jang, Y., Lee, M.H., Lee, J., Jung, J., Lee, S.H., Yang, D.J., Kim, B.W., Son, H., Lee, B., and Chang, S. (2014). TRPM2 mediates the lysophosphatidic acid-induced neurite retraction in the developing brain. Pflügers Arch. 466, 1987-1998.
    Pubmed CrossRef
  26. Jiang, C., Zhai, M., Yan, D., Li, D., Li, C., Zhang, Y., Xiao, L., Xiong, D., Deng, Q., and Sun, W. (2017). Dietary menthol-induced TRPM8 activation enhances WAT “browning” and ameliorates diet-induced obesity. Oncotarget. 8, 75114.
    Pubmed KoreaMed CrossRef
  27. Julius, D. (2013). TRP channels and pain. Annu Rev Cell Dev Biol. 29, 355-384.
    Pubmed CrossRef
  28. Kahn-Kirby, A.H., Dantzker, J.L., Apicella, A.J., Schafer, W.R., Browse, J., Bargmann, C.I., and Watts, J.L. (2004). Specific polyunsaturated fatty acids drive TRPV-dependent sensory signaling in vivo. Cell. 119, 889-900.
    Pubmed CrossRef
  29. Kang, J.H., Tsuyoshi, G., Han, I.S., Kawada, T., Kim, Y.M., and Yu, R. (2010). Dietary capsaicin reduces obesity-induced insulin resistance and hepatic steatosis in obese mice fed a high-fat diet. Obesity. 18, 780-787.
    Pubmed CrossRef
  30. Kim, M.J., Son, H.J., Song, S.H., Jung, M., Kim, Y., and Rhyu, M.R. (2013). The TRPA1 agonist, methyl syringate suppresses food intake and gastric emptying. PLoS One. 8, e71603.
    Pubmed KoreaMed CrossRef
  31. Kim, S.H., Lee, Y., Akitake, B., Woodward, O.M., Guggino, W.B., and Montell, C. (2010). Drosophila TRPA1 channel mediates chemical avoidance in gustatory receptor neurons. Proc Natl Acad Sci. 107, 8440-8445.
    Pubmed KoreaMed CrossRef
  32. Kraft, R., Grimm, C., Frenzel, H., and Harteneck, C. (2006). Inhibition of TRPM2 cation channels by N-(p-amylcinnamoyl) anthranilic acid. Br J Pharmacol. 148, 264-273.
    Pubmed KoreaMed CrossRef
  33. Kumar, A., Goswami, L., and Goswami, C. (2013). Importance of TRP channels in pain: implications for stress. Front Biosci (Schol Ed). 5, 19-38.
    Pubmed CrossRef
  34. Kusudo, T., Wang, Z., Mizuno, A., Suzuki, M., and Yamashita, H. (2011). TRPV4 deficiency increases skeletal muscle metabolic capacity and resistance against diet-induced obesity. J Appl Physiol. 112, 1223-1232.
    Pubmed CrossRef
  35. Lanner, J.T., Bruton, J.D., Katz, A., and Westerblad, H. (2008). Ca2+ and insulin-mediated glucose uptake. Curr Opin Pharmacol. 8, 339-345.
    Pubmed CrossRef
  36. Lee, E., Jung, D.Y., Kim, J.H., Patel, P.R., Hu, X., Lee, Y., Azuma, Y., Wang, H.F., Tsitsilianos, N., and Shafiq, U. (2015). Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance. FASEB J. 29, 3182-3192.
    Pubmed KoreaMed CrossRef
  37. Lee, J.E., Kim, Y., Kim, K.H., Lee, D.Y., and Lee, Y. (2016). Contribution of Drosophila TRPA1 to metabolism. PLoS One. 11, e0152935.
    Pubmed KoreaMed CrossRef
  38. Lee, Y. (2013). Contribution of Drosophila TRPA1-expressing neurons to circadian locomotor activity patterns. PLoS One. 8, e85189.
    Pubmed KoreaMed CrossRef
  39. Leibiger, I.B., Leibiger, B., and Berggren, P.O. (2002). Insulin feedback action on pancreatic β-cell function. FEBS Lett. 532, 1-6.
    Pubmed CrossRef
  40. Liedtke, W., Choe, Y., Martí-Renom, M.A., Bell, A.M., Denis, C.S., Hudspeth, A., Friedman, J.M., and Heller, S. (2000). Vanilloid receptor-related osmotically activated channel (VR-OAC), a candidate vertebrate osmoreceptor. Cell. 103, 525-535.
    Pubmed KoreaMed CrossRef
  41. Liu, D., Zhu, Z., and Tepel, M. (2008). The role of transient receptor potential channels in metabolic syndrome. Hypertens Res. 31, 1989-1995.
    Pubmed CrossRef
  42. Liu, H., Dear, A.E., Knudsen, L.B., and Simpson, R.W. (2009). A long-acting glucagon-like peptide-1 analogue attenuates induction of plasminogen activator inhibitor type-1 and vascular adhesion molecules. J Endocrinol. 201, 59-66.
    Pubmed CrossRef
  43. Liu, M., Huang, W., Wu, D., and Priestley, J.V. (2006). TRPV1, but not P2X3, requires cholesterol for its function and membrane expression in rat nociceptors. Eur J Neurosci. 24, 1-6.
    Pubmed CrossRef
  44. Liu, P., Shah, B.P., Croasdell, S., and Gilbertson, T.A. (2011). Transient receptor potential channel type M5 is essential for fat taste. J Neurosci. 31, 8634-8642.
    Pubmed KoreaMed CrossRef
  45. Lyall, V., Heck, G.L., Vinnikova, A.K., Ghosh, S., Phan, T.H.T., Alam, R.I., Russell, O.F., Malik, S.A., Bigbee, J.W., and DeSimone, J.A. (2004). The mammalian amiloride-insensitive non-specific salt taste receptor is a vanilloid receptor-1 variant. J Physiol. 558, 147-159.
    Pubmed KoreaMed CrossRef
  46. Macpherson, L.J., Dubin, A.E., Evans, M.J., Marr, F., Schultz, P.G., Cravatt, B.F., and Patapoutian, A. (2007). Noxious compounds activate TRPA1 ion channels through covalent modification of cysteines. Nature. 445, 541-545.
    Pubmed CrossRef
  47. Marshall, N.J., Liang, L., Bodkin, J., Dessapt-Baradez, C., Nandi, M., Collot-Teixeira, S., Smillie, S.J., Lalgi, K., Fernandes, E.S., and Gnudi, L. (2012). A role for TRPV1 in influencing the onset of cardiovascular disease in obesity. Hypertension. 61, 246-252.
    Pubmed CrossRef
  48. Masuda, Y., Haramizu, S., Oki, K., Ohnuki, K., Watanabe, T., Yazawa, S., Kawada, T., Hashizume, S., and Fushiki, T. (2003). Upregulation of uncoupling proteins by oral administration of capsiate, a nonpungent capsaicin analog. J Appl Physiol. 95, 2408-2415.
    Pubmed CrossRef
  49. Matsuura, H., Sokabe, T., Kohno, K., Tominaga, M., and Kadowaki, T. (2009). Evolutionary conservation and changes in insect TRP channels. BMC Evol Biol. 9, 228.
    Pubmed KoreaMed CrossRef
  50. Monet, M., Gkika, D., Lehen’kyi, V., Pourtier, A., Abeele, F.V., Bidaux, G., Juvin, V., Rassendren, F., Humez, S., and Prevarsakaya, N. (2009). Lysophospholipids stimulate prostate cancer cell migration via TRPV2 channel activation. Biochim Biophys Acta. 1793, 528-539.
    Pubmed CrossRef
  51. Montell, C. (2005). The TRP superfamily of cation channels. Sci STKE. 2005, re3.
    Pubmed CrossRef
  52. Montell, C. and Rubin, G.M. (1989). Molecular characterization of the Drosophila trp locus: a putative integral membrane protein required for phototransduction. Neuron. 2, 1313-1323.
    Pubmed CrossRef
  53. Moqrich, A., Hwang, S.W., Earley, T.J., Petrus, M.J., Murray, A.N., Spencer, K.S., Andahazy, M., Story, G.M., and Patapoutian, A. (2005). Impaired thermosensation in mice lacking TRPV3, a heat and camphor sensor in the skin. Science. 307, 1468-1472.
    Pubmed CrossRef
  54. Moran, M.M., McAlexander, M.A., Bíró, T., and Szallasi, A. (2011). Transient receptor potential channels as therapeutic targets. Nat Rev Drug Discov. 10, 601.
    Pubmed CrossRef
  55. Morita, H., Honda, A., Inoue, R., Ito, Y., Abe, K., Nelson, M.T., and Brayden, J.E. (2007). Membrane stretch-induced activation of a TRPM4-like nonselective cation channel in cerebral artery myocytes. J Pharmacol. 103, 417-426.
    Pubmed CrossRef
  56. Motter, A.L. and Ahern, G.P. (2008). TRPV1-null mice are protected from diet-induced obesity. FEBS Lett. 582, 2257-2262.
    Pubmed KoreaMed CrossRef
  57. Nijenhuis, T., Hoenderop, J.G., and Bindels, R.J. (2005). TRPV5 and TRPV6 in Ca2+ (re)absorption: regulating Ca2+ entry at the gate. Pflügers Arch. 451, 181-192.
    Pubmed CrossRef
  58. Nilius, B. and Owsianik, G. (2011). The transient receptor potential family of ion channels. Genome Biol. 12, 218.
    Pubmed KoreaMed CrossRef
  59. Nilius, B., Owsianik, G., Voets, T., and Peters, J.A. (2007). Transient receptor potential cation channels in disease. Physiol Rev. 87, 165-217.
    Pubmed CrossRef
  60. Nilius, B. and Szallasi, A. (2014). Transient receptor potential channels as drug targets: from the science of basic research to the art of medicine. Pharmacol Rev. 66, 676-814.
    Pubmed CrossRef
  61. Nozawa, K., Kawabata-Shoda, E., Doihara, H., Kojima, R., Okada, H., Mochizuki, S., Sano, Y., Inamura, K., Matsushime, H., and Koizumi, T. (2009). TRPA1 regulates gastrointestinal motility through serotonin release from enterochromaffin cells. Proc Natl Acad Sci. 106, 3408-3413.
    Pubmed KoreaMed CrossRef
  62. Palmer, R.K., Atwal, K., Bakaj, I., Carlucci-Derbyshire, S., Buber, M.T., Cerne, R., Cortés, R.Y., Devantier, H.R., Jorgensen, V., and Pawlyk, A. (2010). Triphenylphosphine oxide is a potent and selective inhibitor of the transient receptor potential melastatin-5 ion channel. Assay Drug Dev Technol. 8, 703-713.
    Pubmed CrossRef
  63. Palmer, R.K. and Lunn, C.A. (2013). TRP channels as targets for therapeutic intervention in obesity: focus on TRPV1 and TRPM5. Curr Top Med Chem. 13, 247-257.
    Pubmed CrossRef
  64. Parks, D.J., Parsons, W.H., Colburn, R.W., Meegalla, S.K., Ballentine, S.K., Illig, C.R., Qin, N., Liu, Y., Hutchinson, T.L., and Lubin, M.L. (2010). Design and optimization of benzimidazole-containing transient receptor potential melastatin 8 (TRPM8) antagonists. J Med Chem. 54, 233-247.
    Pubmed CrossRef
  65. Peier, A.M., Moqrich, A., Hergarden, A.C., Reeve, A.J., Andersson, D.A., Story, G.M., Earley, T.J., Dragoni, I., McIntyre, P., and Bevan, S. (2002). A TRP channel that senses cold stimuli and menthol. Cell. 108, 705-715.
    Pubmed CrossRef
  66. Perraud, A.L., Takanishi, C.L., Shen, B., Kang, S., Smith, M.K., Schmitz, C., Knowles, H.M., Ferraris, D., Li, W., and Zhang, J. (2005). Accumulation of free ADP-ribose from mitochondria mediates oxidative stress-induced gating of TRPM2 cation channels. J Biol Chem. 280, 6138-6148.
    Pubmed CrossRef
  67. Qin, N., Neeper, M.P., Liu, Y., Hutchinson, T.L., Lubin, M.L., and Flores, C.M. (2008). TRPV2 is activated by cannabidiol and mediates CGRP release in cultured rat dorsal root ganglion neurons. J Neurosci. 28, 6231-6238.
    Pubmed KoreaMed CrossRef
  68. Rabini, R.A., Galassi, R., Fumelli, P., Dousset, N., Solera, M.L., Valdiguie, P., Curatola, G., Ferretti, G., Taus, M., and Mazzanti, L. (1994). Reduced Na(+)-K(+)-ATPase activity and plasma lysophosphatidylcholine concentrations in diabetic patients. Diabetes. 43, 915-919.
    Pubmed CrossRef
  69. Ramsey, I.S., Delling, M., and Clapham, D.E. (2006). An introduction to TRP channels. Annu Rev Physiol. 68, 619-647.
    Pubmed CrossRef
  70. Razavi, R., Chan, Y., Afifiyan, F.N., Liu, X.J., Wan, X., Yantha, J., Tsui, H., Tang, L., Tsai, S., and Santamaria, P. (2006). TRPV1+ sensory neurons control β cell stress and islet inflammation in autoimmune diabetes. Cell. 127, 1123-1135.
    Pubmed CrossRef
  71. Riera, C.E., Huising, M.O., Follett, P., Leblanc, M., Halloran, J., Van Andel, R., de Magalhaes Filho, C.D., Merkwirth, C., and Dillin, A. (2014). TRPV1 pain receptors regulate longevity and metabolism by neuropeptide signaling. Cell. 157, 1023-1036.
    Pubmed CrossRef
  72. Rossato, M., Granzotto, M., Macchi, V., Porzionato, A., Petrelli, L., Calcagno, A., Vencato, J., De Stefani, D., Silvestrin, V., and Rizzuto, R. (2014). Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol. 383, 137-146.
    Pubmed CrossRef
  73. Saito, M. and Yoneshiro, T. (2013). Capsinoids and related food ingredients activating brown fat thermogenesis and reducing body fat in humans. Curr Opin Lipidol. 24, 71-77.
    Pubmed CrossRef
  74. Seabrook, G.R., Sutton, K.G., Jarolimek, W., Hollingworth, G.J., Teague, S., Webb, J., Clark, N., Boyce, S., Kerby, J., and Ali, Z. (2002). Functional properties of the high-affinity TRPV1 (VR1) vanilloid receptor antagonist (4-hydroxy-5-iodo-3-methoxyphenylacetate ester) iodo-resiniferatoxin. J Pharmacol Exp Ther. 303, 1052-1060.
    Pubmed CrossRef
  75. Shen, D., Wang, X., Li, X., Zhang, X., Yao, Z., Dibble, S., Dong, X.P., Yu, T., Lieberman, A.P., and Showalter, H.D. (2012). Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release. Nature Commun. 3, 731.
    Pubmed KoreaMed CrossRef
  76. Smeets, A.J. and Westerterp-Plantenga, M.S. (2009). The acute effects of a lunch containing capsaicin on energy and substrate utilisation, hormones, and satiety. Euro J Nutr. 48, 229-234.
    Pubmed KoreaMed CrossRef
  77. Sohn, J.W., Elmquist, J.K., and Williams, K.W. (2013). Neuronal circuits that regulate feeding behavior and metabolism. Trends Neurosci. 36, 504-512.
    Pubmed KoreaMed CrossRef
  78. Sprous, D. and Palmer, R.K. (2010). The T1R2/T1R3 sweet receptor and TRPM5 ion channel: taste targets with therapeutic potential. Prog Mol Biol Transl Sci. 91, 151-208.
    Pubmed CrossRef
  79. Suzuki, M., Mizuno, A., Kodaira, K., and Imai, M. (2003). Impaired pressure sensation in mice lacking TRPV4. J Biol Chem. 278, 22664-22668.
    Pubmed CrossRef
  80. Svobodova, B. and Groschner, K. (2016). Mechanisms of lipid regulation and lipid gating in TRPC channels. Cell Calcium. 59, 271-279.
    Pubmed CrossRef
  81. Takezawa, R., Cheng, H., Beck, A., Ishikawa, J., Launay, P., Kubota, H., Kinet, J.P., Fleig, A., Yamada, T., and Penner, R. (2006). A pyrazole derivative potently inhibits lymphocyte Ca2+ influx and cytokine production by facilitating TRPM4 channel activity. Mol Pharmacol. 69, 1413-1420.
    Pubmed CrossRef
  82. Tani, Y., Fujioka, T., Sumioka, M., Furuichi, Y., Hamada, H., and Watanabe, T. (2004). Effects of capsinoid on serum and liver lipids in hyperlipidemic rats. J Nutr Sci Vitaminol. 50, 351-355.
    Pubmed CrossRef
  83. Tiede, S., Cantz, M., Spranger, J., and Braulke, T. (2006). Missense mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTA) in a patient with mucolipidosis II induces changes in the size and cellular distribution of GNPTG. Hum Mutat. 27, 830-831.
    Pubmed CrossRef
  84. Tiede, S., Muschol, N., Reutter, G., Cantz, M., Ullrich, K., and Braulke, T. (2005). Missense mutations in N-acetylglucosamine-1-phosphotransferase α/β subunit gene in a patient with mucolipidosis III and a mild clinical phenotype. Am J Med Genet A. 137, 235-240.
    Pubmed CrossRef
  85. Togashi, K., Hara, Y., Tominaga, T., Higashi, T., Konishi, Y., Mori, Y., and Tominaga, M. (2006). TRPM2 activation by cyclic ADP-ribose at body temperature is involved in insulin secretion. EMBO J. 25, 1804-1815.
    Pubmed KoreaMed CrossRef
  86. Trevisani, M., Siemens, J., Materazzi, S., Bautista, D.M., Nassini, R., Campi, B., Imamachi, N., Andre, E., Patacchini, R., and Cottrell, G.S. (2007). 4-Hydroxynonenal, an endogenous aldehyde, causes pain and neurogenic inflammation through activation of the irritant receptor TRPA1. Proc Natl Acad Sci. 104, 13519-13524.
    Pubmed KoreaMed CrossRef
  87. Uchida, K., Dezaki, K., Yoneshiro, T., Watanabe, T., Yamazaki, J., Saito, M., Yada, T., Tominaga, M., and Iwasaki, Y. (2017). Involvement of thermosensitive TRP channels in energy metabolism. J Physiol Sci. 67, 549-560.
    Pubmed CrossRef
  88. Uchida, K. and Tominaga, M. (2011). The role of thermosensitive TRP (transient receptor potential) channels in insulin secretion. Endocr J. 58, 1021-1028.
    Pubmed CrossRef
  89. Venkatachalam, K. and Montell, C. (2007). TRP channels. Annu Rev Biochem. 76, 387-417.
    Pubmed KoreaMed CrossRef
  90. Venkatachalam, K., Wong, C.O., and Montell, C. (2013). Feast or famine: role of TRPML in preventing cellular amino acid starvation. Autophagy. 9, 98-100.
    Pubmed KoreaMed CrossRef
  91. Walder, R.Y., Yang, B., Stokes, J.B., Kirby, P.A., Cao, X., Shi, P., Searby, C.C., Husted, R.F., and Sheffield, V.C. (2009). Mice defective in Trpm6 show embryonic mortality and neural tube defects. Hum Mol Genet. 18, 4367-4375.
    Pubmed KoreaMed CrossRef
  92. Wang, H. and Siemens, J. (2015). TRP ion channels in thermosensation, thermoregulation and metabolism. Temperature. 2, 178-187.
    Pubmed KoreaMed CrossRef
  93. Wang, X., Miyares, R.L., and Ahern, G.P. (2005). Oleoylethanolamide excites vagal sensory neurones, induces visceral pain and reduces short-term food intake in mice via capsaicin receptor TRPV1. J Physiol. 564, 541-547.
    Pubmed KoreaMed CrossRef
  94. Wanner, S.P., Garami, A., and Romanovsky, A.A. (2011). Hyperactive when young, hypoactive and overweight when aged: connecting the dots in the story about locomotor activity, body mass, and aging in Trpv1 knockout mice. Aging (Albany NY). 3, 450-457.
    Pubmed KoreaMed CrossRef
  95. Whiting, S., Derbyshire, E., and Tiwari, B. (2014). Could capsaicinoids help to support weight management? A systematic review and meta-analysis of energy intake data. Appetite. 73, 183-188.
    Pubmed CrossRef
  96. Williams, K.W. and Elmquist, J.K. (2012). From neuroanatomy to behavior: central integration of peripheral signals regulating feeding behavior. Nat Neurosci. 15, 1350.
    Pubmed KoreaMed CrossRef
  97. Wong, C.O., Li, R., Montell, C., and Venkatachalam, K. (2012). Drosophila TRPML is required for TORC1 activation. Curr Biol. 22, 1616-1621.
    Pubmed KoreaMed CrossRef
  98. Wu, X., Eder, P., Chang, B., and Molkentin, J.D. (2010). TRPC channels are necessary mediators of pathologic cardiac hypertrophy. Proc Natl Acad Sci. 107, 7000-7005.
    Pubmed KoreaMed CrossRef
  99. Xiao, B., Dubin, A.E., Bursulaya, B., Viswanath, V., Jegla, T.J., and Patapoutian, A. (2008). Identification of transmembrane domain 5 as a critical molecular determinant of menthol sensitivity in mammalian TRPA1 channels. J Neurosci. 28, 9640-9651.
    Pubmed KoreaMed CrossRef
  100. Xu, H., Blair, N.T., and Clapham, D.E. (2005). Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J Neurosci. 25, 8924-8937.
    Pubmed CrossRef
  101. Ye, L., Kleiner, S., Wu, J., Sah, R., Gupta, R.K., Banks, A.S., Cohen, P., Khandekar, M.J., Boström, P., and Mepani, R.J. (2012). TRPV4 is a regulator of adipose oxidative metabolism, inflammation, and energy homeostasis. Cell. 151, 96-110.
    Pubmed KoreaMed CrossRef
  102. Yoshioka, M., Lim, K., Kikuzato, S., Kiyonaga, A., Tanaka, H., Shindo, M., and Suzuki, M. (1995). Effects of red-pepper diet on the energy metabolism in men. J Nutr Sci Vitaminol. 41, 647-656.
    Pubmed CrossRef
  103. Yu, X., Yu, M., Liu, Y., and Yu, S. (2016). TRP channel functions in the gastrointestinal tract. Semin Immunopathol. 38, 385-396.
    Pubmed CrossRef
  104. Zhang, L.L., Yan Liu, D., Ma, L.Q., Luo, Z.D., Cao, T.B., Zhong, J., Yan, Z.C., Wang, L.J., Zhao, Z.G., and Zhu, S.J. (2007). Activation of transient receptor potential vanilloid type-1 channel prevents adipogenesis and obesity. Circ Res. 100, 1063-1070.
    Pubmed CrossRef
  105. Zhang, Z., Zhang, W., Jung, D.Y., Ko, H.J., Lee, Y., Friedline, R.H., Lee, E., Jun, J., Ma, Z., and Kim, F. (2012). TRPM2 Ca2+ channel regulates energy balance and glucose metabolism. Am J Physiol Endocrinol Metab. 302, E807-E816.
    Pubmed KoreaMed CrossRef
  106. Zhu, Z., Luo, Z., Ma, S., and Liu, D. (2011). TRP channels and their implications in metabolic diseases. Pflügers Arch. 461, 211-223.
    Pubmed CrossRef
  107. Zsombok, A. and Derbenev, A.V. (2016). TRP channels as therapeutic targets in diabetes and obesity. Pharmaceuticals. 9, 50.
    Pubmed KoreaMed CrossRef
Mol. Cells
Sep 30, 2023 Vol.46 No.9, pp. 527~572
COVER PICTURE
Chronic obstructive pulmonary disease (COPD) is marked by airspace enlargement (emphysema) and small airway fibrosis, leading to airflow obstruction and eventual respiratory failure. Shown is a microphotograph of hematoxylin and eosin (H&E)-stained histological sections of the enlarged alveoli as an indicator of emphysema. Piao et al. (pp. 558-572) demonstrate that recombinant human hyaluronan and proteoglycan link protein 1 (rhHAPLN1) significantly reduces the extended airspaces of the emphysematous alveoli by increasing the levels of TGF-β receptor I and SIRT1/6, as a previously unrecognized mechanism in human alveolar epithelial cells, and consequently mitigates COPD.
Current Issue Archives

Share this article on

  • line

Related articles in Mol. Cells

Molecules and Cells

eISSN 0219-1032
qr-code Download