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 TRPC4(3 is regulated by phospholipase C (PLC) signaling and is especially maintained by phosphatidylino-sitol 4,5-bisphosphate (PIP2). In this study, we present the regulation mechanism of the TRPC4 channel with PIP2 hydrolysis which is mediated by a channel-bound PLC delta 1 but not by the GqPCR signaling pathway. Our electrophysiological recordings dem-onstrate that the Ca2+ via an open TRPC4 channel activates PLC delta 1 in the physiological range, and it causes the decrease of current amplitude. The existence of PLC delta 1 ac-celerated PIP2 depletion when the channel was activated by an agonist. Interestingly, PLC delta 1 mutants which have lost the ability to regulate PIP2 level failed to reduce the TRPC4 current amplitude. Our results demonstrate that TRPC4 self-regulates its activ-ity by allowing Ca2+ ions into the cell and promoting the PIP2 hydrolyzing activity of PLC delta 1.