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.