Department of Physiology, College of Medicine, Seoul National University, Seoul, 03080, Republic of Korea.
Department of Physiology, College of Veterinary Medicine, Chungnam National University, Daejeon, 34134, Republic of Korea.
Cell Calcium. 2024 Nov;123:102932. doi: 10.1016/j.ceca.2024.102932. Epub 2024 Jul 27.
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.
瞬时受体电位经典型 3（TRPC3）是一种钙通透性、非选择性阳离子通道，已知其受磷脂酶 C（PLC）介导的信号通路的组成部分调节，如 Ca2+、二酰基甘油（DAG）和磷脂酰肌醇 4,5-二磷酸（PI（4,5）P）。然而，这些调节剂的分子门控机制尚未完全了解，特别是其对 PI（4,5）P 的调节，尽管该通道在心血管病理生理学中非常重要。最近，Clarke 等人（2024）使用分子动力学模拟和膜片钳技术报道了 PI（4,5）P 是 TRPC3 的正调节剂。他们证明了 TRPC3 的多步门控机制，PI（4,5）P 与位于前 S1/S1 连接点的脂质结合位点结合，并通过 TRP 螺旋和 S4-S5 连接子之间的盐桥将 PI（4,5）P 感应传播到孔域。
