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


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.
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH.
Sathya D
SD
Unudurthi
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH.
Xiangqiong
X
Wu
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH.
Lan
L
Qian
Department of Molecular Virology, Immunology & Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH.
Foued
F
Amari
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH.
Birce
B
Onal
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH.
Ning
N
Li
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH.
Michael A
MA
Makara
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.
Sakima A
SA
Smith
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH.
Jedidiah
J
Snyder
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH.
Vadim V
VV
Fedorov
Department of Molecular Virology, Immunology & Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH.
Vincenzo
V
Coppola
Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD.
Mark E
ME
Anderson
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Physiology & Cell Biology, The Ohio State University Wexner Medical Center, Columbus, OH Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.
Peter J
PJ
Mohler
The Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, OH Department of Internal Medicine, The Ohio State University Wexner Medical Center, Columbus, OH Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH thomas.hund@osumc.edu.
Thomas J
TJ
Hund
D000200:Action Potentials / Q000502:physiology; D000818:Animals; D004452:Echocardiography; D051379:Mice; D018345:Mice, Knockout; D024683:Potassium Channels, Tandem Pore Domain / Q000172:deficiency / Q000502:physiology*; D012849:Sinoatrial Node / Q000502:physiology*
D024683:Potassium Channels, Tandem Pore Domain; C103742:potassium channel protein TREK-1
K channel; TREK‐1; automaticity; sinoatrial node; spectrin