Phosphatidylinositol-(4, 5)-bisphosphate regulates calcium gating of small-conductance cation channel TMEM16F

Significance TMEM16F, a small-conductance Ca2+ -activated cation channel that permeates Ca2+ , is required for the Ca2+ -activated phospholipid scramblase activity. The Ca2+ -activated Ca2+ -conductance mediated by TMEM16F constitutes positive feedback, with potentially deleterious outcomes if not tightly regulated. We performed electrophysiological recordings to show that Ca2+ -gating of TMEM16F depends on TMEM16F interaction with PIP2 , a minor yet functionally significant phospholipid constituent in the plasma membrane. Elevated intracellular Ca2+ promotes PIP2 hydrolysis by membrane-tethered phospholipases, thereby causing TMEM16F inactivation and likely rendering protection from Ca2+ -overloading and cytotoxicity. Given that TMEM16F plays significant roles in blood coagulation and immune responses, our study will help reveal how signaling pathways involving phosphoinositides could potentially contribute to these physiological processes.