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Differential regulation of ca2+-activated cl− channel tmem16a splice variants by membrane pi(4,5)p2

Title
Differential regulation of ca2+-activated cl− channel tmem16a splice variants by membrane pi(4,5)p2
Authors
Ko, WooriSuh, Byung-Chang
DGIST Authors
Ko, Woori; Suh, Byung-Chang
Issue Date
2021-04
Citation
International Journal of Molecular Sciences, 22(8), 4088
Type
Article
Author Keywords
Ca2+-activated Cl− channelPI(4,5)P2Splice variantsTMEM16A
Keywords
PHOSPHATIDYLINOSITOL 4,5-BISPHOSPHATEVOLTAGEPHOSPHATASEMODULATIONPROTEINSKINETICSROLES
ISSN
1661-6596
Abstract
TMEM16A is a Ca2+-activated Cl− channel that controls broad cellular processes ranging from mucus secretion to signal transduction and neuronal excitability. Recent studies have reported that membrane phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2 ) is an important cofactor that allosterically regulates TMEM16A channel activity. However, the detailed regulatory actions of PIP2 in splice variants of TMEM16A remain unclear. Here, we demonstrated that the attenuation of membrane phosphoinositide levels selectively inhibited the current amplitude of the TMEM16A(ac) isoform by decreasing the slow, but not instantaneous, Cl− currents, which are independent of the membrane potential and specific to PI(4,5)P2 depletion. The attenuation of endogenous PI(4,5)P2 levels by the activation of Danio rerio voltage-sensitive phosphatase (Dr-VSP) decreased the Cl− currents of TMEM16A(ac) but not the TMEM16A(a) isoform, which was abolished by the co-expression of PIP 5-kinase type-1γ (PIPKIγ). Using the rapamycin-inducible dimerization of exogenous phosphoinositide phosphatases, we further revealed that the stimulatory effects of phosphoinositide on TMEM16A(ac) channels were similar in various membrane potentials and specific to PI(4,5)P2, not PI4P and PI(3,4,5)P3 . Finally, we also confirmed that PI(4,5)P2 resynthesis is essential for TMEM16A(ac) recovery from Dr-VSP-induced current inhibition. Our data demonstrate that membrane PI(4,5)P2 selectively modulates the gating of the TMEM16A(ac) channel in an agonistic manner, which leads to the upregulation of TMEM16A(ac) functions in physiological conditions. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
URI
http://hdl.handle.net/20.500.11750/13998
DOI
10.3390/ijms22084088
Publisher
MDPI AG
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:
Collection:
Department of Brain SciencesLaboratory of Brain Signal and Synapse Research1. Journal Articles


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