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