Article: Phosphatidylinositol 4,5-Bisphosphate and Cholesterol Regulators of the Calcium-Activated Chloride Channels TMEM16A and TMEM16B.
Advances in experimental medicine and biology
2023 Volume 1422, Page(s) 279–304
Abstract: Chloride fluxes through homo-dimeric calcium-activated channels TMEM16A and TMEM16B are critical to blood pressure, gastrointestinal motility, hormone, fluid and electrolyte secretion, pain sensation, sensory transduction, and neuronal and muscle ... ...
Abstract | Chloride fluxes through homo-dimeric calcium-activated channels TMEM16A and TMEM16B are critical to blood pressure, gastrointestinal motility, hormone, fluid and electrolyte secretion, pain sensation, sensory transduction, and neuronal and muscle excitability. Their gating depends on the voltage-dependent binding of two intracellular calcium ions to a high-affinity site formed by acidic residues from α-helices 6-8 in each monomer. Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), a low-abundant lipid of the inner leaflet, supports TMEM16A function; it allows TMEM16A to evade the down-regulation induced by calcium, poly-L-lysine, or PI(4,5)P2 5-phosphatase. In stark contrast, adding or removing PI(4,5)P2 diminishes or increases TMEM16B function, respectively. PI(4,5)P2-binding sites on TMEM16A, and presumably on TMEM16B, are on the cytosolic side of α-helices 3-5, opposite the calcium-binding sites. This modular structure suggested that PI(4,5)P2 and calcium cooperate to maintain the conductive state in TMEM16A. Cholesterol, the second-largest constituent of the plasma membrane, also regulates TMEM16A though the mechanism, functional outcomes, binding site(s), and effects on TMEM16A and TMEM16B remain unknown. |
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MeSH term(s) | Humans ; Chloride Channels/genetics ; Chloride Channels/chemistry ; Chloride Channels/metabolism ; Anoctamin-1/metabolism ; Phosphatidylinositols ; Calcium/metabolism ; Cholesterol ; Calcium Channels ; HEK293 Cells |
Chemical Substances | Chloride Channels ; Anoctamin-1 ; Phosphatidylinositols ; Calcium (SY7Q814VUP) ; Cholesterol (97C5T2UQ7J) ; Calcium Channels |
Language | English |
Publishing date | 2023-03-29 |
Publishing country | United States |
Document type | Journal Article |
ISSN | 2214-8019 ; 0065-2598 |
ISSN (online) | 2214-8019 |
ISSN | 0065-2598 |
DOI | 10.1007/978-3-031-21547-6_10 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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