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

Korean J Physiol Pharmacol. 2023 Mar 1;27(2):187-196. doi: 10.4196/kjpp.2023.27.2.187.


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 (PIP2). In this study, we present the regulation mechanism of the TRPC4 channel with PIP2 hydrolysis which is mediated by a channel-bound PLCδ1 but not by the GqPCR signaling pathway. Our electrophysiological recordings demonstrate that the Ca2+ via an open TRPC4 channel activates PLCδ1 in the physiological range, and it causes the decrease of current amplitude. The existence of PLCδ1 accelerated PIP2 depletion when the channel was activated by an agonist. Interestingly, PLCδ1 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 activity by allowing Ca2+ ions into the cell and promoting the PIP2 hydrolyzing activity of PLCδ1.

Keywords: Calcium; Fluorescence resonance energy transfer; Phosphatidylinositols; Phospholipase C delta; Transient receptor potential channels.

Grant support

FUNDING This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Korean government (2020R1A2C1012670, 2021R1A4A2001857) (I.S.) and the Education and Research Encouragement Fund of Seoul National University Hospital (I.S.). J. Kim. was supported by the BK21 program from the Ministry of Education.