Brennan, Sean, Makwana, Samir, Chen, Shen, McGuinness, Lauren R, Sweihi, Moustafa, Whitmore, Jacob A, Elghayesh, Mahmoud E, Martin, Christopher A, Sheikh, Noorann, Patel, Manish et al (show 4 more authors)
(2026)
Cardiac ventricular Kir6.1 ATP-sensitive potassium channels: an overlooked effector of cardioprotection
FRONTIERS IN PHYSIOLOGY, 17.
1808226-.
ISSN 1664-042X, 1664-042X
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PDF
Brennan et al Kir6.1 Cardioprotection 2026 Frontiers Accepted 31.03.2026.pdf - Author Accepted Manuscript Available under License Creative Commons Attribution. Download (3MB) | Preview |
Abstract
Introduction – Adenosine triphosphate (ATP)-sensitive potassium (K<inf>ATP</inf>) channels are octameric structures, comprising a pore-forming homotetramer of Kir6.1 or Kir6.2, with 4 accessory sulphonylurea receptor (SUR) subunits. The canonical ventricular K<inf>ATP</inf> channel is the highly ATP-sensitive Kir6.2/SUR2A complex, which is largely inactive under normal physiological conditions. Pharmacological activation of K<inf>ATP</inf> channels is cardioprotective, but cardioprotective interventions, such as ischaemic preconditioning, preserve cellular ATP and cause a delay in Kir6.2/SUR2A activation. Recently we demonstrated functional expression of a second, Kir6.1-containing, ventricular K<inf>ATP</inf> channel population that is constitutively active and modulates action potential duration. Here, we characterise the effects of cardioprotective stimuli on this newly identified K<inf>ATP</inf> channel population. Methods – Patch-clamp recordings were used to investigate channel activity, in control cardiomyocytes, following adenosine or K<inf>ATP</inf> modulator treatment, and in cardiomyocytes isolated from ischaemic-preconditioned whole hearts. Metabolic inhibition and washout experiments, together with whole-heart coronary ligation protocols, were used to assess markers of cardioprotection. Results – Cardioprotective stimuli increased Kir6.1 channel activity leading to action potential shortening, reduced Ca2+ accumulation and preserved contractile function, all hallmarks of a cardioprotected phenotype. Furthermore, inherent cardioprotection in female-derived cardiomyocytes correlates to increased Kir6.1 activity. Discussion – These findings suggest that the two functionally distinct populations of ventricular K<inf>ATP</inf> channels play different roles in cardioprotection. Kir6.1-containing channels acutely control action potential duration, limiting Ca 2+ accumulation in the early stages of metabolic stress, whilst the canonical Kir6.2/SUR2A channel imparts late-stage protection against catastrophic ATP depletion. This role for Kir6.1 in cardioprotection suggests that this channel should be considered in drug development pipelines where channel block may inhibit endogenous cardioprotection.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ATP-sensitive potassium channel, cardiomyocytes, cardioprotection, KATP channels, Kir6.1 |
| Divisions: | Faculty of Health & Life Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences > Inst. Life Courses & Medical Sciences (T&R staff) Faculty of Health & Life Sciences > Inst. Life Courses & Medical Sciences > Cardiovascular & Metabolic Medicine |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 10 Apr 2026 15:55 |
| Last Modified: | 02 Jun 2026 06:55 |
| DOI: | 10.3389/fphys.2026.1808226 |
| Related Websites: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3197919 |
| Disclaimer: | The University of Liverpool is not responsible for content contained on other websites from links within repository metadata. Please contact us if you notice anything that appears incorrect or inappropriate. |
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