Department of Pharmacology, Medical University of Vienna, Vienna, Austria.
Division of Medical Physics and Biophysics, Medical University of Graz, Graz, Austria.
Nat Commun. 2024 Jun 18;15(1):5220. doi: 10.1038/s41467-024-49396-6.
The transient receptor potential canonical type 3 (TRPC3) channel plays a pivotal role in regulating neuronal excitability in the brain via its constitutive activity. The channel is intricately regulated by lipids and has previously been demonstrated to be positively modulated by PIP. Using molecular dynamics simulations and patch clamp techniques, we reveal that PIP predominantly interacts with TRPC3 at the L3 lipid binding site, located at the intersection of pre-S1 and S1 helices. We demonstrate that PIP sensing involves a multistep mechanism that propagates from L3 to the pore domain via a salt bridge between the TRP helix and S4-S5 linker. Notably, we find that both stimulated and constitutive TRPC3 activity require PIP. These structural insights into the function of TRPC3 are invaluable for understanding the role of the TRPC subfamily in health and disease, in particular for cardiovascular diseases, in which TRPC3 channels play a major role.
瞬时受体电位经典型 3 型 (TRPC3) 通道通过其组成型活性在大脑中调节神经元兴奋性方面发挥着关键作用。该通道受到脂质的复杂调节，先前已被证明可被 PIP 正向调节。使用分子动力学模拟和膜片钳技术，我们揭示了 PIP 主要与位于 S1 螺旋前 S1 和 S1 螺旋交汇处的 L3 脂质结合位点相互作用。我们证明 PIP 感应涉及一个多步骤机制，该机制通过 TRP 螺旋和 S4-S5 接头之间的盐桥从 L3 传播到孔域。值得注意的是，我们发现刺激和组成型 TRPC3 活性都需要 PIP。这些对 TRPC3 功能的结构见解对于理解 TRPC 亚家族在健康和疾病中的作用是非常宝贵的，特别是对于心血管疾病，其中 TRPC3 通道起着主要作用。
