Abstract
The TMEM16A/anoctamin-1 calcium-activated chloride channel (CaCC) contributes to a range of vital functions, such as the control of vascular tone and epithelial ion transport. The channel is a founding member of a family of 10 proteins (TMEM16x) with varied functions; some members (i.e., TMEM16A and TMEM16B) serve as CaCCs, while others are lipid scramblases, combine channel and scramblase function, or perform additional cellular roles. TMEM16x proteins are typically activated by agonist-induced Ca2+ release evoked by Gq-protein-coupled receptor (GqPCR) activation; thus, TMEM16x proteins link Ca2+-signalling with cell electrical activity and/or lipid transport. Recent studies demonstrate that a range of other cellular factors—including plasmalemmal lipids, pH, hypoxia, ATP and auxiliary proteins—also control the activity of the TMEM16A channel and its paralogues, suggesting that the TMEM16x proteins are effectively polymodal sensors of cellular homeostasis. Here, we review the molecular pathophysiology, structural biology, and mechanisms of regulation of TMEM16x proteins by multiple cellular factors.
Highlights
Introduction toTMEM16x PhysiologyPolymodal Control of TMEM16xThe TMEM16x eukaryotic protein family (HUGO gene nomenclature: Anoctamin) is composed of 10 paralogues in mammals that share high sequence homology while forming a functionally diverse group of proteins
TM6), effectively blocking the top of what constitutes the scramblase groove in scramblase homologues [105,107,108] (Figure 1). This results in the formation of a protein-enclosed ion-conductive pore in TMEM16A that is for the most part shielded from the membrane, but which might be partly accessible to lipids on its intracellular side [105,107,108], where the detachment of TM4 and TM6 forms a funnel-shaped vestibule that has portions directly exposed to the cytoplasm and the lipid bilayer
A series of mechanisms can explain the combined ion channel and scramblase function of some TMEM16x proteins; these include (1) the ‘alternating pore–cavity’ model, which implies that ions permeate through an intermediate, semi-closed conformation of the lipid/ion permeation pathway that is nonconductive to lipids, but permeable to ions [113], and (2) the proteolipidic pore model, which implies that ions and lipids are transported through the fully open cavity lined with lipid headgroups [158]
Summary
The TMEM16x eukaryotic protein family (HUGO gene nomenclature: Anoctamin) is composed of 10 paralogues in mammals that share high sequence homology while forming a functionally diverse group of proteins. TMEM16x proteins may (1) form Ca2+ activated Cl− channels (CaCCs) (TMEM16A and B) [1]; (2) function as lipid scramblases, which facilitate bidirectional movement of lipids across the cell membranes, possibly in combination with non-selective ion channel activity (TMEM16D, E, F, K and J) [2,3,4,5,6,7,8]; or (3). Some TMEM16x (TMEM16C, G, and H) proteins play cellular roles other than serving as ion channels or lipid scramblases. TMEM16J is another TMEM16x with reported intracellular localisation [31,80,81]; heterologous expression in HEK293T cells promotes plasma membrane expression, where the TMEM16J works as a cation channel activated by a cAMP-dependent protein kinase. TMEM16J is overexpressed in pancreatic cancer cells [86], in gastrointestinal cancer [87], and in oesophageal squamous-cell carcinoma (ESCC) [81], and is associated with tumour progression [81,86,87]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
