A Phosphoinositide Binding Module Controls TMEM16A Desensitization
58 Pages Posted: 21 Nov 2018 Sneak Peek Status: Under ReviewMore...
Calcium-activated chloride channels (CaCCs) are critical in regulating neural excitability, nociception, smooth muscle contraction, secretion and gut motility. Besides Ca2 - and voltage-dependent activation, another hallmark of TMEM16A-CaCC is time-dependent desensitization or rundown, the mechanism of which is unclear. Here we report that phosphatidylinositol-(4,5)bisphosphate (PIP2) controls TMEM16A desensitization by stabilizing the channel pore, which is formed by a PIP2 binding ‘regulatory module’ of transmembrane segments (TMs) 3-5 and a ‘Ca2 -binding module’ of TMs6-8. Under sub-micromolar Ca2 , PIP2 dissociation from the ‘regulatory module’ leads to transient pore collapse and desensitization, which can be rapidly reversed by exogenous PIP2, higher Ca2 or voltage. Sustained channel opening under saturating Ca2 requires PIP2 to prevent the persistent pore collapse and desensitization, whose recovery needs prolonged exogenous PIP2 exposure. The PIP2-dependent, bimodal desensitization mechanism and the proposed modular design of TMEM16A pore can shine lights on understanding the structure, function, regulation and physiology of TMEM16 family.
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