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

• Published in: British journal of pharmacology Vol. 181; no. 18; p. 3380
• Main Authors: Brennan, Sean, Chen, Shen, Makwana, Samir, Esposito, Simona, McGuinness, Lauren R, Alnaimi, Abrar I M, Sims, Mark W, Patel, Manish, Aziz, Qadeer, Ojake, Leona, Roberts, James A, Sharma, Parveen, Lodwick, David, Tinker, Andrew, Barrett-Jolley, Richard, Dart, Caroline, Rainbow, Richard D
• Format: Journal Article
• Language: English
• Published: England 01.09.2024
• Subjects: Action Potentials - drug effects; Animals; Heart Ventricles - cytology; Heart Ventricles - drug effects; Heart Ventricles - metabolism; KATP Channels - metabolism; Male; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - metabolism; Patch-Clamp Techniques; Potassium Channels, Inwardly Rectifying - antagonists & inhibitors; Potassium Channels, Inwardly Rectifying - metabolism; Rats; Rats, Sprague-Dawley; Sarcolemma - drug effects; Sarcolemma - metabolism; cardiomyocytes; Kir6.1; KATP channels; ATP‐sensitive potassium channel
• ISSN: 1476-5381
• DOI: 10.1111/bph.16390

The canonical K 6.2/SUR2A ventricular K 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 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 channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviours of a constitutively active K 6.1-containing K 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 6.1-containing channels. These K 6.1-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 channels: constitutively active K 6.1-containing channels that play an important role in fine-tuning the action potential and K 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 6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.