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A Phosphoinositide Binding Module Controls TMEM16A Desensitization

58 Pages Posted: 21 Nov 2018 Sneak Peek Status: Under Review

See all articles by Son C. Le

Son C. Le

Duke University - Department of Biochemistry

Zhiguang Jia

University of Massachusetts Amherst - Department of Chemistry

Jianhan Chen

University of Massachusetts Amherst - Department of Chemistry

Huanghe Yang

Duke University - Department of Biochemistry

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Abstract

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.

Suggested Citation

Le, Son C. and Jia, Zhiguang and Chen, Jianhan and Yang, Huanghe, A Phosphoinositide Binding Module Controls TMEM16A Desensitization (November 20, 2018). Available at SSRN: https://ssrn.com/abstract=3287790 or http://dx.doi.org/10.2139/ssrn.3287790
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Son C. Le

Duke University - Department of Biochemistry

100 Fuqua Drive
Durham, NC 27708-0204
United States

Zhiguang Jia

University of Massachusetts Amherst - Department of Chemistry

Amherst, MA 01003
United States

Jianhan Chen

University of Massachusetts Amherst - Department of Chemistry

Amherst, MA 01003
United States

Huanghe Yang (Contact Author)

Duke University - Department of Biochemistry ( email )

100 Fuqua Drive
Durham, NC 27708-0204
United States

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