Cardiac ventricular Kir6.1 ATP-sensitive potassium channels: an overlooked effector of cardioprotection

Adenosine triphosphate (ATP)-sensitive potassium (K_ATP) 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_ATP channel is the highly ATP-sensitive Kir6.2/SUR2A complex, which is largely inactive under normal physiological conditions. Pharmacological activation of K_ATP 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_ATP channel population that is constitutively active and modulates action potential duration. Here, we characterise the effects of cardioprotective stimuli on this newly identified K_ATP channel population.

Patch-clamp recordings were used to investigate channel activity, in control cardiomyocytes, following adenosine or K_ATP 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.

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.

These findings suggest that the two functionally distinct populations of ventricular K_ATP 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.