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J Biol Chem. 2018 Jun 8;293(23):8912-8921. doi: 10.1074/jbc.RA118.002775. Epub 2018 Apr 17.

ATP-sensitive potassium channels in the sinoatrial node contribute to heart rate control and adaptation to hypoxia.

Author information

1
From the Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, EC1M 6BQ, United Kingdom.
2
the Department of Clinical Physiology & Echocardiography, CHU Lille and the University of Lille, EGID, INSERM UMR1011, F-59000 Lille, France.
3
the Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universität Erlangen-Nürnberg, 91054 Erlangen, Germany, and.
4
From the Heart Centre, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, London, EC1M 6BQ, United Kingdom, a.tinker@qmul.ac.uk.

Abstract

ATP-sensitive potassium channels (KATP) contribute to membrane currents in many tissues, are responsive to intracellular metabolism, and open as ATP falls and ADP rises. KATP channels are widely distributed in tissues and are prominently expressed in the heart. They have generally been observed in ventricular tissue, but they are also expressed in the atria and conduction tissues. In this study, we focused on the contribution and role of the inwardly rectifying KATP channel subunit, Kir6.1, in the sinoatrial node (SAN). To develop a murine, conduction-specific Kir6.1 KO model, we selectively deleted Kir6.1 in the conduction system in adult mice (cKO). Electrophysiological data in single SAN cells indicated that Kir6.1 underlies a KATP current in a significant proportion of cells and influences early repolarization during pacemaking, resulting in prolonged cycle length. Implanted telemetry probes to measure heart rate and electrocardiographic characteristics revealed that the cKO mice have a slow heart rate, with episodes of sinus arrest in some mice. The PR interval (time between the onset of the P wave to the beginning of QRS complex) was increased, suggesting effects on the atrioventricular node. Ex vivo studies of whole heart or dissected heart regions disclosed impaired adaptive responses of the SAN to hypoxia, and this may have had long-term pathological consequences in the cKO mice. In conclusion, Kir6.1-containing KATP channels in the SAN have a role in excitability, heart rate control, and the electrophysiological adaptation of the SAN to hypoxia.

KEYWORDS:

ATP-sensitive potassium channel; heart; heart rate; hypoxia; ion channel; membrane biophysics; membrane function; potassium channel; sinoatrial node

PMID:
29666184
PMCID:
PMC5995522
DOI:
10.1074/jbc.RA118.002775
[Indexed for MEDLINE]
Free PMC Article

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