Identification and characterisation of functional K_ir6.1-containing ATP-sensitive potassium channels in the cardiac...

The canonical K_ir6.2/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_ir6.1-containing K_ATP channel in ventricular cardiomyocytes.

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.

Our data show a ventricular K⁺ conductance whose biophysical characteristics and response to pharmacological modulation were consistent with K_ir6.1-containing channels. These K_ir6.1-containing channels lack the ATP-sensitivity of the canonical channels and are constitutively active.

We conclude there are two functionally distinct populations of ventricular K_ATP channels: constitutively active K_ir6.1-containing channels that play an important role in fine-tuning the action potential and K_ir6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether K_ir6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.