Novel finding for screening Small G proteins influencing transient receptor potential canonical 4 (TRPC4) channels

Abstract

Canonical transient receptor potential 4 (TRPC4) channels are calcium-permeable, non-selective cation channels that are widely distributed in mammalian cells. It is generally speculated that TRPC4 channels are activated by Gq/11-PLC pathway or directly activated by Gi/o proteins. Although many mechanistic studies regarding TRPC4 have dealt with heterotrimeric G-proteins, here, we first report the functional relationship between TRPC4 and small GTPase. We performed patch clamp, western blotting, and FRET technique. Rab proteins, Rasd1, Rasd2, and Rit protein increased without GTPS. Rasd1 selectively activated TRPC4 channels and it was the Ras protein among small G protein families that can potently activate TRPC4 channels. For this to occur, it was found that certain population of functional Gαi1 protein is essential. Meanwhile, dexamethasone, a synthetic gluco-corticoid and anti-inflammatory drug were known to increase mRNA level of Rasd1 in pancreatic β-cells. We have found that dexamethasone triggers TRPC4-like cationic current in INS-1 cells via increasing protein expression level of Rasd1. This relationship among dexamethasone, Rasd1 and TRPC4 could suggest a new therapeutic agent for hospitalized diabetes mellitus (DM) patients with prolonged dexamethasone prescription.