Ginseng Gintonin Contains Ligands for GPR40 and GPR55

Abstract

Gintonin, a novel ginseng-derived glycolipoprotein complex, has an exogenous ligand for lysophosphatidic acid (LPA) receptors. However, recent lipid analysis of gintonin has shown that gintonin also contains other bioactive lipids besides LPAs, including linoleic acid and lysophosphatidylinositol (LPI). Linoleic acid, a free fatty acid, and LPI are known as ligands for the G-protein coupled receptors (GPCR), GPR40, and GPR55, respectively. We, herein, investigated whether gintonin could serve as a ligand for GPR40 and GPR55, using the insulin-secreting beta cell-derived cell line INS-1 and the human prostate cancer cell line PC-3, respectively. Gintonin dose-dependently enhanced insulin secretion from INS-1 cells. Gintonin-stimulated insulin secretion was partially inhibited by a GPR40 receptor antagonist but not an LPA1/3 receptor antagonist and was down-regulated by small interfering RNA (siRNA) against GPR40. Gintonin dose-dependently induced [Ca2+]i transients and Ca2+-dependent cell migration in PC-3 cells. Gintonin actions in PC-3 cells were attenuated by pretreatment with a GPR55 antagonist and an LPA1/3 receptor antagonist or by down-regulating GPR55 with siRNA. Taken together, these results demonstrated that gintonin-mediated insulin secretion by INS-1 cells and PC-3 cell migration were regulated by the respective activation of GPR40 and GPR55 receptors. These findings indicated that gintonin could function as a ligand for both receptors. Finally, we demonstrated that gintonin contained two more GPCR ligands, in addition to that for LPA receptors. Gintonin, with its multiple GPCR ligands, might provide the molecular basis for the multiple pharmacological actions of ginseng.

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“…Gintonin is a novel lysophosphatidic acid (LPA)–ginseng protein complex naturally derived from ginseng . It contains an exogenous G-protein-coupled lysophosphatidic acid receptor (LPAR) ligand capable of repressing inflammation.…”

BRET analysis reveals interaction between the lysophosphatidic acid receptor LPA2 and the lysophosphatidylinositol receptor GPR55 in live cells

“…Circulating LPA and LPI are known to bind the specific GPCRs LPA and GPR55 receptor, respectively, and elicit various cellular responses [36]. Although limited studies to date have focused on the intracellular effects of simultaneous activity of the two ligands, studies on gintonin, a ginseng-derived glycolipoprotein complex containing LPA and LPI, report possible crosstalk between the two receptors [37].…”

Ginseng gintonin, aging societies, and geriatric brain diseases

“… 37 Recently, it was demonstrated that gintonin linoleic acid and LPI interact with GPR40 and GPR55 to exhibit cellular effects such as insulin secretion and Ca 2+ -mediated cell migration, respectively. 49 Thus, gintonin contains at least three different ligand complexes for G protein-coupled receptor regulation such as LPA receptors, GPR40, and GPR55 ( Fig. 2 ).…”

“… 49 Interestingly, although the signaling pathways of GPR40 are different from that of LPA receptors, 49 LPA receptors and GPR55 share common signaling pathways, in that activation of both receptors elicits [Ca 2+ ] i transients and induces Ca 2+ -dependent cell migration. 49 Gintonin-mediated activation of GPR55 and LPA receptors is coupled to [Ca 2+ ] i transients through Gα q/11 activation-phospholipase C activation-IP 3 formation-[Ca 2+ ] i transient induction. Thus, gintonin produces second messenger Ca 2+ via LPA receptors and GPR55.…”

“…Recently, gintonin was isolated from ginseng and gintonin acts as an exogenous ligand for the LPA receptors, GPR40 and GPR55. 49 Gintonin attenuates aging related-neurodegenerative diseases such as AD, PD, and HD, 12 , 91 , 92 , 100 and stimulates autophagy in neuronal cells 56 and is a good candidate for ginseng-derived functional foods or natural medicines against aging-related brain diseases. This is important, since AD, PD, and HD are becoming increasingly more prevalent in our aging society, and dramatically increasing compared with other chronic diseases.…”