Gintonin‐Mediated Depolarization of Pacemaker Activity in Cultured Interstitial Cells of Cajal

Abstract

We investigated the effect of gintonin, a novel ginseng‐derived G protein‐coupled lysophosphatidic acid (LPA) receptor ligand, on the pacemaker activity of the interstitial cells of Cajal (ICC) in murine small intestine and GI motility. The whole‐cell patch‐clamp configuration was used to record pacemaker potentials and currents from cultured ICC in the absence or presence of gintonin. In vivo effects of gintonin on GI motility were investigated by measuring the intestinal transit rate (ITR) of Evans blue in normal and streptozotocin (STZ)‐induced diabetic mice. Gintonin caused membrane depolarization but this action was blocked by Ki16425, an LPA1/3 receptor antagonist. Next, we examined the effects of U‐73122, an active PLC inhibitor, and chelerythrine and calphostin, which inhibit PKC. All inhibitors blocked gintonin actions on pacemaker potentials, but not completely. Gintonin‐mediated depolarization was lower in Ca2+‐free than in Ca2+‐containing external solutions and was blocked by thapsigargin. We found that gintonin also activated Ca2+‐activated Cl‐ channels (ANO1), but not TRPM7 channels. In vivo, gintonin (10‐100 mg/kg), not only significantly increased the ITR in normal mice but also ameliorated STZ‐induced diabetic GI motility retardation. Gintonin could be a novel candidate for development as a prokinetic agent that may prevent or alleviate GI motility dysfunctions in human patients.