Periphery Pre-S1 and S1 helix nexus for PIP₂ 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 Ca²⁺, diacylglycerol (DAG) and phosphatidylinositol 4,5-biphosphate (PI(4,5)P₂). However, the molecular gating mechanism by these regulators is not yet fully understood, especially its regulation by PI(4,5)P₂, despite the importance of this channel in cardiovascular pathophysiology. Recently, Clarke et al. (2024) have reported that PI(4,5)P₂ 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)P₂ to the lipid binding site located at the pre-S1/S1 nexus, and the propagation of PI(4,5)P₂ sensing to the pore domain via a salt bridge between the TRP helix and the S4-S5 linker.