Negative self-regulation of transient receptor potential canonical 4 by the specific interaction with phospholipase C-δ1

Transient receptor potential canonical (TRPC) channels are non-selective calcium-permeable cation channels. It is suggested that TRPC4β is regulated by phospholipase C (PLC) signaling and is especially maintained by phosphatidylinositol 4,5-bisphosphate (PIP(2)). In this study, we present the regulation mechanism of the TRPC4 channel with PIP(2) hydrolysis which is mediated by a channel-bound PLCδ1 but not by the G(q)PCR signaling pathway. Our electrophysiological recordings demonstrate that the Ca(2+) via an open TRPC4 channel activates PLCδ1 in the physiological range, and it causes the decrease of current amplitude. The existence of PLCδ1 accelerated PIP(2) depletion when the channel was activated by an agonist. Interestingly, PLCδ1 mutants which have lost the ability to regulate PIP(2) level failed to reduce the TRPC4 current amplitude. Our results demonstrate that TRPC4 self-regulates its activity by allowing Ca(2+) ions into the cell and promoting the PIP(2) hydrolyzing activity of PLCδ1.