Identification and characterisation of functional K ir 6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane.

Background and Purpose: The canonical K _ir 6.2/SUR2A ventricular K _ATP channel is highly ATP-sensitive and remains closed under normal physiological conditions. These channels activate only when prolonged metabolic compromise causes significant ATP depletion and then shortens the action potential to reduce contractile activity. Pharmacological activation of K _ATP channels is cardioprotective, but physiologically, it is difficult to understand how these channels protect the heart if they only open under extreme metabolic stress. The presence of a second K _ATP channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active K _ir 6.1-containing K _ATP channel in ventricular cardiomyocytes.
Experimental Approach: Patch-clamp recordings from rat ventricular myocytes in combination with well-defined pharmacological modulators was used to characterise these newly identified K ⁺ channels. Action potential recording, calcium (Fluo-4) fluorescence measurements and video edge detection of contractile function were used to assess functional consequences of channel modulation.
Key Results: Our data show a ventricular K ⁺ conductance whose biophysical characteristics and response to pharmacological modulation were consistent with K _ir 6.1-containing channels. These K _ir 6.1-containing channels lack the ATP-sensitivity of the canonical channels and are constitutively active.
Conclusion and Implications: We conclude there are two functionally distinct populations of ventricular K _ATP channels: constitutively active K _ir 6.1-containing channels that play an important role in fine-tuning the action potential and K _ir 6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether K _ir 6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.
(© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)