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Molecular Mechanisms of Activation and Regulation of ANO1-Encoded Ca2+-Activated Cl- Channels.

Hawn, MB; Akin, E; Hartzell, HC; Greenwood, IA; Leblanc, N (2002) Molecular Mechanisms of Activation and Regulation of ANO1-Encoded Ca2+-Activated Cl- Channels. Channels (Austin), 15 (1). pp. 569-603. ISSN 1933-6969
SGUL Authors: Greenwood, Iain Andrew

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Ca2+-activated Cl- channels (CaCCs) perform a multitude of functions including the control of cell excitability, regulation of cell volume and ionic homeostasis, exocrine and endocrine secretion, fertilization, amplification of olfactory sensory function, and control of smooth muscle cell contractility. CaCCs are the translated products of two members (ANO1 and ANO2, also known as TMEM16A and TMEM16B) of the Anoctamin family of genes comprising ten paralogs. This review focuses on recent progress in understanding the molecular mechanisms involved in the regulation of ANO1 by cytoplasmic Ca2+, post-translational modifications, and how the channel protein interacts with membrane lipids and protein partners. After first reviewing the basic properties of native CaCCs, we then present a brief historical perspective highlighting controversies about their molecular identity in native cells. This is followed by a summary of the fundamental biophysical and structural properties of ANO1. We specifically address whether the channel is directly activated by internal Ca2+ or indirectly through the intervention of the Ca2+-binding protein Calmodulin (CaM), and the structural domains responsible for Ca2+- and voltage-dependent gating. We then review the regulation of ANO1 by internal ATP, Calmodulin-dependent protein kinase II-(CaMKII)-mediated phosphorylation and phosphatase activity, membrane lipids such as the phospholipid phosphatidyl-(4,5)-bisphosphate (PIP2), free fatty acids and cholesterol, and the cytoskeleton. The article ends with a survey of physical and functional interactions of ANO1 with other membrane proteins such as CLCA1/2, inositol trisphosphate and ryanodine receptors in the endoplasmic reticulum, several members of the TRP channel family, and the ancillary Κ+ channel β subunits KCNE1/5.

Item Type: Article
Additional Information: © 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Keywords: ANO1, Anoctamin-1, CaMKII, PIP2, TMEM16A, calcium binding, calcium-activated chloride channel, phosphorylation, regulation, structure, 0299 Other Physical Sciences, Biochemistry & Molecular Biology
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Channels (Austin)
ISSN: 1933-6969
Language: eng
27 September 2002Published
7 September 2021Published Online
29 August 2021Accepted
Publisher License: Creative Commons: Attribution 4.0
Project IDFunderFunder ID
P20GM130459National Institutes of Health
R01HL146054National Institutes of Health
R01EY014852National Institutes of Health
R01GM132598National Institutes of Health
UNSPECIFIEDBritish Heart Foundation
PubMed ID: 34488544
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