PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker

• Published in: Nature communications 2024-06, Vol.15 (1), p.5220-13
• Main Authors: Clarke, Amy, Skerjanz, Julia, Gsell, Mathias A. F., Wiedner, Patrick, Erkan-Candag, Hazel, Groschner, Klaus, Stockner, Thomas, Tiapko, Oleksandra
• Format: Article
• Language: English
• Subjects: 631/45/269/1146; 631/535/1267; 631/57/2270/1140; 9/74; 9/97; Binding sites; Cardiovascular diseases; Excitability; Helices; Humanities and Social Sciences; Lipids; Molecular dynamics; multidisciplinary; Mutagenesis; Phosphatidylinositol 4,5-diphosphate; Science; Science (multidisciplinary); Simulation; Transient receptor potential proteins
• ISSN: 2041-1723; 2041-1723
• 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 2 . Using molecular dynamics simulations and patch clamp techniques, we reveal that PIP 2 predominantly interacts with TRPC3 at the L3 lipid binding site, located at the intersection of pre-S1 and S1 helices. We demonstrate that PIP 2 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 2 . 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. TRPC3 regulates neuronal excitability via its constitutive activity. Using MD simulations and patch clamp techniques, Clarke et al. show that PIP2 controls TRPC3 via a salt bridge formed between the TRP helix and the S4-S5 linker, affecting both stimulated and constitutive TRPC3 activities.