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.

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 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.

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.