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Author Notes:

Dayue Darrel Duan, Laboratory of Cardiovascular Phenomics, Department of Pharmacology, Center for Molecular Medicine, School of Medicine University of Nevada, Reno, NV 89557, dduan@medicine.nevada.edu.

Or: Dr. Zhi-Ren Zhang and Dr. Dan Zhao, Departments of Clinical Pharmacy and Cardiology, The 2nd Affiliated Hospital, Harbin Medical University, Key Laboratories of Education Ministry for Myocardial Ischemia Mechanism and Treatment, Harbin 150086, P.R. China. zhaod@rocketmail.com

Zhen Ye and Ming-Ming Wu contributed equally to this work.

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Research Funding:

This study was supported by Key Project of Chinese National Program for Fundamental Research and Development (973 Program 2012CB517803, 2014CB542401 to Z. Z.); NSFC (30871007, 81070217 to Z. Z.); Doctoral Tutor Foundation of Ministry of Education (20122307110008 to Z. Z.); the Natural Science Foundation of Heilongjiang Province (ZD200807-01, ZD200807-02 to Z. Z. and QC2010097 to D. Z.); Overseas Talent Foundation of Department of Education, Heilongjiang Province (1154HZ11 to Z. Z.); and Science Research Foundation of Graduate School of HMU (YJSCX2011-336 to Z. Y.).

This study was also supported by AHA Western States Affiliate Grant-in-Aid (11GRNT7610161 to D. D.); and the NIH Grant (HL106256 to D. D.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Physiology
  • CANINE VENTRICULAR MYOCYTES
  • SMOOTH-MUSCLE-CELLS
  • DELAYED AFTERDEPOLARIZATIONS
  • SINGLE PURKINJE
  • ATRIAL MYOCYTES
  • CL-CHANNELS
  • TMEM16A
  • HEART
  • CURRENTS
  • PHENOMICS

Characterization of Cardiac Anoctamin1 Ca2+-Activated Chloride Channels and Functional Role in Ischemia-Induced Arrhythmias

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Journal Title:

Journal of Cellular Physiology

Volume:

Volume 230, Number 2

Publisher:

, Pages 337-346

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Anoctamin1 (ANO1) encodes a Ca2+-activated chloride (Cl-) channel (CaCC) in variety tissues of many species. Whether ANO1 expresses and functions as a CaCC in cardiomyocytes remain unknown. The objective of this study is to characterize the molecular and functional expression of ANO1 in cardiac myocytes and the role of ANO1-encoded CaCCs in ischemia-induced arrhythmias in the heart. Quantitative real-time RT-PCR, immunofluorescence staining assays, and immunohistochemistry identified the molecular expression, location, and distribution of ANO1 in mouse ventricular myocytes (mVMs). Patch-clamp recordings combined with pharmacological analyses found that ANO1 was responsible for a Ca2+-activated Cl- current (ICl.Ca) in cardiomyocytes. Myocardial ischemia led to a significant increase in the current density of ICl.Ca, which was inhibited by a specific ANO1 inhibitor, T16Ainh-A01, and an antibody targeting at the pore area of ANO1. Moreover, cardiomyocytes isolated from mice with ischemia-induced arrhythmias had an accelerated early phase 1 repolarization of action potentials (APs) and a deeper "spike and dome" compared to control cardiomyocytes from non-ischemia mice. Application of the antibody targeting at ANO1 pore prevented the ischemia-induced early phase 1 repolarization acceleration and caused a much shallower "spike and dome". We conclude that ANO1 encodes CaCC and plays a significant role in the phase 1 repolarization of APs in mVMs. The ischemia-induced increase in ANO1 expression may be responsible for the increased density of ICl.Ca in the ischemic heart and may contribute, at least in part, to ischemia-induced arrhythmias.

Copyright information:

© 2014 Wiley Periodicals, Inc.

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