Two-Pore K+ Channel TREK-1 Regulates Sinoatrial Node Membrane Excitability.

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.

• Authors: Sathya D Unudurthi, Xiangqiong Wu, Lan Qian, Foued Amari, Birce Onal, Ning Li, Michael A Makara, Sakima A Smith, Jedidiah Snyder, Vadim V Fedorov, Vincenzo Coppola, Mark E Anderson, Peter J Mohler, Thomas J Hund
• Journal: Journal of the American Heart Association (J Am Heart Assoc) Vol. 5 Issue 4 Pg. e002865 (Apr 20 2016) ISSN: 2047-9980 [Electronic] England
• PMID: 27098968 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Chemical References

• Potassium Channels, Tandem Pore Domain
• potassium channel protein TREK-1

Topics

• Action Potentials (physiology)
• Animals
• Echocardiography
• Mice
• Mice, Knockout
• Potassium Channels, Tandem Pore Domain (deficiency, physiology)
• Sinoatrial Node (physiology)