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Mol. Cells 2012; 34(6): 563-572

Published online December 31, 2012

© The Korean Society for Molecular and Cellular Biology

Gintonin, a Ginseng-Derived Novel Ingredient, Evokes Long-Term Potentiation through N-methyl-D-aspartic Acid Receptor Activation: Involvement of LPA Receptors

Tae-Joon Shin, Hyeon-Joong Kim, Byeong-Jae Kwon, Sun-Hye Choi, Hyun-Bum Kim, Sung-Hee Hwang, Byung-Hwan Lee, Sang-Mok Lee, R. Suzanne Zukin, Ji-Ho Park, Hyoung-Chun Kim4, Hyewhon Rhim, Joon-Hee Lee, and Seung-Yeol Nah

1Department of Physiology, College of Veterinary Medicine and Veterinary Science Research Institute, and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea, 2Graduate School of East-West Medical Science and Research Institute of Medical Nutrition, Kyung Hee University, Yongin 446-701, Korea, 3Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA, 4Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea, 5Life Science Division, Korea Institute of Science and Technology, Seoul 130-701, Korea, 6Department of Physical Therapy, Daebul University, Yeongam 526-702, Korea, 7These authors contributed equally to this work.

Abstract

Ginseng has been shown to have memory-improving effects in human. However, little is known about the active
components and the molecular mechanisms underlying its effects. Recently, we isolated novel lysophosphatidic acids
(LPAs)-ginseng protein complex derived from ginseng, gintonin. Gintonin activates G protein-coupled LPA receptors
with high affinity. Gintonin activated Ca2+-activated Cl-channels in Xenopus oocytes through the activation of
endogenous LPA receptor. In the present study, we investigated whether the activation of LPA receptor by gintonin
is coupled to the regulation of N-methyl-D-aspartic acid (NMDA) receptor channel activity in Xenopus oocytes expressing
rat NMDA receptors. The NMDA receptor-mediated ion current (INMDA) was measured using the two-electrode
voltage-clamp technique. In oocytes injected with cRNAs encoding NMDA receptor subunits, gintonin enhanced
INMDA in a concentration-dependent manner. Gintonin-mediated INMDA enhancement was blocked by Ki16425,
an LPA1/3 receptor antagonist. Gintonin action was blocked by a PLC inhibitor, IP3 receptor antagonist, Ca2+
chelator, and a tyrosine kinase inhibitor. The site-directed mutation of Ser1308 of the NMDA receptor, which is phosphorylated
by protein kinase C (PKC), to an Ala residue, or co-expression of receptor protein tyrosine phosphatase
with the NMDA receptor attenuated gintonin action. Moreover, gintonin treatment elicited a transient elevation of
[Ca2+]i in cultured hippocampal neurons and elevated longterm potentiation (LTP) in both concentration-dependent
manners in rat hippocampal slices. Gintonin-mediated LTP induction was abolished by Ki16425. These results indicate
that gintonin-mediated INMDA potentiation and LTP induction in the hippocampus via the activation of LPA
receptor might be responsible for ginseng-mediated improvement of memory-related brain functions.

Keywords ginseng, gintonin, LPA receptors, N-methyl-D-aspartic acid receptor, LTP

Article

Research Article

Mol. Cells 2012; 34(6): 563-572

Published online December 31, 2012

Copyright © The Korean Society for Molecular and Cellular Biology.

Gintonin, a Ginseng-Derived Novel Ingredient, Evokes Long-Term Potentiation through N-methyl-D-aspartic Acid Receptor Activation: Involvement of LPA Receptors

Tae-Joon Shin, Hyeon-Joong Kim, Byeong-Jae Kwon, Sun-Hye Choi, Hyun-Bum Kim, Sung-Hee Hwang, Byung-Hwan Lee, Sang-Mok Lee, R. Suzanne Zukin, Ji-Ho Park, Hyoung-Chun Kim4, Hyewhon Rhim, Joon-Hee Lee, and Seung-Yeol Nah

1Department of Physiology, College of Veterinary Medicine and Veterinary Science Research Institute, and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Korea, 2Graduate School of East-West Medical Science and Research Institute of Medical Nutrition, Kyung Hee University, Yongin 446-701, Korea, 3Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, Bronx, NY 10461, USA, 4Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon 200-701, Korea, 5Life Science Division, Korea Institute of Science and Technology, Seoul 130-701, Korea, 6Department of Physical Therapy, Daebul University, Yeongam 526-702, Korea, 7These authors contributed equally to this work.

Abstract

Ginseng has been shown to have memory-improving effects in human. However, little is known about the active
components and the molecular mechanisms underlying its effects. Recently, we isolated novel lysophosphatidic acids
(LPAs)-ginseng protein complex derived from ginseng, gintonin. Gintonin activates G protein-coupled LPA receptors
with high affinity. Gintonin activated Ca2+-activated Cl-channels in Xenopus oocytes through the activation of
endogenous LPA receptor. In the present study, we investigated whether the activation of LPA receptor by gintonin
is coupled to the regulation of N-methyl-D-aspartic acid (NMDA) receptor channel activity in Xenopus oocytes expressing
rat NMDA receptors. The NMDA receptor-mediated ion current (INMDA) was measured using the two-electrode
voltage-clamp technique. In oocytes injected with cRNAs encoding NMDA receptor subunits, gintonin enhanced
INMDA in a concentration-dependent manner. Gintonin-mediated INMDA enhancement was blocked by Ki16425,
an LPA1/3 receptor antagonist. Gintonin action was blocked by a PLC inhibitor, IP3 receptor antagonist, Ca2+
chelator, and a tyrosine kinase inhibitor. The site-directed mutation of Ser1308 of the NMDA receptor, which is phosphorylated
by protein kinase C (PKC), to an Ala residue, or co-expression of receptor protein tyrosine phosphatase
with the NMDA receptor attenuated gintonin action. Moreover, gintonin treatment elicited a transient elevation of
[Ca2+]i in cultured hippocampal neurons and elevated longterm potentiation (LTP) in both concentration-dependent
manners in rat hippocampal slices. Gintonin-mediated LTP induction was abolished by Ki16425. These results indicate
that gintonin-mediated INMDA potentiation and LTP induction in the hippocampus via the activation of LPA
receptor might be responsible for ginseng-mediated improvement of memory-related brain functions.

Keywords: ginseng, gintonin, LPA receptors, N-methyl-D-aspartic acid receptor, LTP

Mol. Cells
Sep 30, 2022 Vol.45 No.9, pp. 603~672
COVER PICTURE
The Target of Rapamycin Complex (TORC) is a central regulatory hub in eukaryotes, which is well conserved in diverse plant species, including tomato (Solanum lycopersicum). Inhibition of TORC genes (SlTOR, SlLST8, and SlRAPTOR) by VIGS (virus-induced gene silencing) results in early fruit ripening in tomato. The red/ orange tomatoes are early-ripened TORC-silenced fruits, while the green tomato is a control fruit. Top, left, control fruit (TRV2-myc); top, right, TRV2-SlLST8; bottom, left, TRV2-SlTOR; bottom, right, TRV2-SlRAPTOR(Choi et al., pp. 660-672).

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