Ca²⁺/Calmodulin-Dependent Protein Kinase Ⅱ γ-Dependent Serine727 Phosphorylation Is Required for TMEM16A Ca²⁺-Activated Cl⁻ Channel Regulation in Cerebrovascular Cells

• Lin Cai-Xia

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

• Lv Xiao-Fei

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

• Yuan Feng

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

• Li Xiang-Yu

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

• Ma Ming-Ming

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

• Liu Can-Zhao

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

• Zhou Jia-Guo

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

• Wang Guan-Lei

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

• Guan Yong-Yuan

  Cardiac and Cerebral Vascular Research Center, Department of Pharmacology, Zhongshan School of Medicine, Sun Yat-sen University

書誌事項

タイトル別名

• Ca²⁺/Calmodulin-Dependent Protein Kinase II γ-Dependent Serine727 Phosphorylation Is Required for TMEM16A Ca²⁺-Activated Cl⁻ Channel Regulation in Cerebrovascular Cells

抄録

Background:TMEM16A is a critical component of Ca²⁺-activated chloride channels (CaCCs) and mediates basilar arterial smooth muscle cell (BASMC) proliferation in hypertensive cerebrovascular remodeling. CaMKII is a negative regulator of CaCC, and four CaMKII isoforms (α, β, γ and δ) are expressed in vasculature; however, it is unknown which and how CaMKII isoforms affect TMEM16A-associated CaCC and BASMC proliferation. Methods and Results:Patch clamp and small interfering RNA (siRNA) knockdown of different CaMKII isoforms revealed that only CaMKIIγ inhibited native Ca²⁺-activated chloride currents (I_Cl.Ca) in BASMCs. The TMEM16A overexpression evoked TMEM16A Cl⁻current and inhibited angiotensin II (Ang II)-induced proliferation in BASMCs. The co-immunoprecipitation and pull-down assay indicated an interaction between CaMKIIγ and TMEM16A protein. TMEM16A Cl⁻current was modulated by CaMKIIγ phosphorylation at serine residues in TMEM16A. Serine525 and Serine727 in TMEM16A were mutated to alanine, and only mutation at Ser727 (S727A) reversed the CaMKIIγ inhibition of the TMEM16A Cl⁻current. Phosphomimetic mutation S727D markedly decreased TMEM16A Cl⁻current and reversed TMEM16A-mediated suppression of BASMC proliferation, mimicking the inhibitory effects of CaMKIIγ on TMEM16A. A significant increase in CaMKIIγ isoform content was observed in parallel to the decrease of TMEM16A and I_Cl.Cain basilar artery proliferative remodeling in Ang II-infused mice. Conclusions:Serine 727 phosphorylation in TMEM16A by CaMKIIγ provides a new mechanism for regulating TMEM16A CaCC activity and Ang II-induced BASMC proliferation.

収録刊行物

• Circulation Journal

  Circulation Journal 82 (3), 903-913, 2018

  一般社団法人 日本循環器学会

キーワード

• CaMKIIγ
• Cerebrovascular remodeling
• Chloride channels
• Serine phosphorylation
• TMEM16A

詳細情報

• CRID: 1390001205108250240
• NII論文ID: 130006394581
• NII書誌ID: AA11591968
• DOI: 10.1253/circj.cj-17-0585
• ISSN: 13474820
• ISSN: 13469843
• NDL書誌ID: 028850478
• PubMed: 29081444
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I028850478
• Web Site: https://www.jstage.jst.go.jp/article/circj/82/3/82_CJ-17-0585/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2018289339
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
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