Two‐Pore K+ Channel TREK‐1 Regulates Sinoatrial Node Membrane Excitability. Issue 4 (20th April 2016)

• Record Type: Journal Article
• Authors: Unudurthi, Sathya D.; Wu, Xiangqiong; Qian, Lan; Amari, Foued; Onal, Birce; Li, Ning; Makara, Michael A.; Smith, Sakima A.; Snyder, Jedidiah; Fedorov, Vadim V.; Coppola, Vincenzo; Anderson, Mark E.; Mohler, Peter J.; Hund, Thomas J.
• Is Part Of: Journal of the American Heart Association. Volume 5:Issue 4(2016)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2016-04-20
• Subjects: automaticity -- K channel -- sinoatrial node -- spectrin -- TREK‐1; Heart -- Diseases -- Periodicals; Cardiovascular system -- Diseases -- Periodicals; Cerebrovascular disease -- Periodicals; Cardiology -- Periodicals; 616.1
• DOI: 10.1161/JAHA.115.002865
• Languages: English
• ISSNs: 2047-9980

Abstract

Abstract : Background: Two‐pore K + channels have emerged as potential targets to selectively regulate cardiac cell membrane excitability; however, lack of specific inhibitors and relevant animal models has impeded the effort to understand the role of 2‐pore K + channels in the heart and their potential as a therapeutic target. The objective of this study was to determine the role of mechanosensitive 2‐pore K + channel family member TREK‐1 in control of cardiac excitability. Methods and Results: Cardiac‐specific TREK‐1–deficient mice (αMHC‐ Kcnk f/f ) were generated and found to have a prevalent sinoatrial phenotype characterized by bradycardia with frequent episodes of sinus pause following stress. Action potential measurements from isolated αMHC‐ Kcnk2 f/f sinoatrial node cells demonstrated decreased background K + current and abnormal sinoatrial cell membrane excitability. To identify novel pathways for regulating TREK‐1 activity and sinoatrial node excitability, mice expressing a truncated allele of the TREK‐1–associated cytoskeletal protein βIV ‐spectrin ( qv 4J mice) were analyzed and found to display defects in cell electrophysiology as well as loss of normal TREK‐1 membrane localization. Finally, the βIV ‐spectrin/TREK‐1 complex was found to be downregulated in the right atrium from a canine model of sinoatrial node dysfunction and in human cardiac disease. Conclusions: These findings identify a TREK‐1–dependent pathway essential for normal sinoatrial node cell excitability that serves as a potential target for selectively regulating sinoatrial node cell function.