Periphery Pre-S1 and S1 helix nexus for PIP at TRPC3 channel.

Transient receptor potential canonical 3 (TRPC3) is a calcium-permeable, non-selective cation channel known to be regulated by components of the phospholipase C (PLC)-mediated signaling pathway, such as Ca, diacylglycerol (DAG) and phosphatidylinositol 4,5-biphosphate (PI(4,5)P). However, the molecular gating mechanism by these regulators is not yet fully understood, especially its regulation by PI(4,5)P, despite the importance of this channel in cardiovascular pathophysiology. Recently, Clarke et al. (2024) have reported that PI(4,5)P is a positive modulator for TRPC3 using molecular dynamics simulations and patch-clamp techniques. They have demonstrated a multistep gating mechanism of TRPC3 with the binding of PI(4,5)P to the lipid binding site located at the pre-S1/S1 nexus, and the propagation of PI(4,5)P sensing to the pore domain via a salt bridge between the TRP helix and the S4-S5 linker.