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. Methods and Results Cardiac‐specific TREK ‐1–deficient mice (α MHC ‐ 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 α MHC ‐ 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 β IV ‐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 β IV ‐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.