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Allosteric modulation of alternatively spliced Ca2+-activated Cl- channels TMEM16A by PI(4,5)P2 and CaMKII

Title
Allosteric modulation of alternatively spliced Ca2+-activated Cl- channels TMEM16A by PI(4,5)P2 and CaMKII
Authors
Ko, Woo RiJung, SeungryoungKim, Kwon WooYeon, Jun HeePark, Cheon-GyuNam, Joo HyunHille, BertilSuh, Byung-Chang
DGIST Authors
Ko, Woo Ri; Jung, Seungryoung; Kim, Kwon Woo; Yeon, Jun Hee; Park, Cheon-Gyu; Nam, Joo Hyun; Hille, Bertil; Suh, Byung-Chang
Issue Date
2020-12
Citation
Proceedings of the National Academy of Sciences of the United States of America, 117(48), 30787-30798
Type
Article
Article Type
Article
Author Keywords
Ca2+-activated Cl- channelTMEM16API(4,5)P-2intracellular ATPsplice variants
Keywords
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATEDEPENDENT REGULATIONCHLORIDE CHANNELSPHOSPHORYLATIONACTIVATIONVOLTAGEPIP2CONDUCTANCESENSITIVITYMECHANISM
ISSN
0027-8424
Abstract
Transmembrane 16A (TMEM16A, anoctamin1), 1 of 10 TMEM16 family proteins, is a Cl− channel activated by intracellular Ca2+ and membrane voltage. This channel is also regulated by the membrane phospholipid phosphatidylinositol 4,5-bisphosphate [PI(4,5) P2]. We find that two splice variants of TMEM16A show different sensitivity to endogenous PI(4,5)P2 degradation, where TMEM16A(ac) displays higher channel activity and more current inhibition by PI(4,5)P2 depletion than TMEM16A(a). These two channel isoforms differ in the alternative splicing of the c-segment (exon 13). The current amplitude and PI(4,5)P2 sensitivity of both TMEM16A(ac) and (a) are significantly strengthened by decreased free cytosolic ATP and by conditions that decrease phosphorylation by Ca2+/calmodulin-dependent protein kinase II (CaMKII). Noise analysis suggests that the augmentation of currents is due to a rise of single-channel current (i), but not of channel number (N) or open probability (PO). Mutagenesis points to arginine 486 in the first intracellular loop as a putative binding site for PI(4,5)P2, and to serine 673 in the third intracellular loop as a site for regulatory channel phosphorylation that modulates the action of PI(4,5)P2. In silico simulation suggests how phosphorylation of S673 allosterically and differently changes the structure of the distant PI(4,5)P2binding site between channel splice variants with and without the c-segment exon. In sum, our study reveals the following: differential regulation of alternatively spliced TMEM16A(ac) and (a) by plasma membrane PI(4,5)P2, modification of these effects by channel phosphorylation, identification of the molecular sites, and mechanistic explanation by in silico simulation. © 2020 National Academy of Sciences. All rights reserved.
URI
http://hdl.handle.net/20.500.11750/12682
DOI
10.1073/pnas.2014520117
Publisher
National Academy of Sciences
Related Researcher
  • Author Suh, Byung-Chang Laboratory of Brain Signal and Synapse Research
  • Research Interests Molecular mechanisms of epilepsy and sensory pain transmission; Signaling mechanism of ion channel regulation and membrane excitability; 분자전기생리; 간질 및 통증의 분자적 기전 연구
Files:
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Collection:
Department of Brain and Cognitive SciencesLaboratory of Brain Signal and Synapse Research1. Journal Articles


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