Identification and characterisation of functional Kir6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane

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Brennan, Sean, Chen, Shen, Makwana, Samir, Esposito, Simona, McGuinness, Lauren, Alnaimi, Abrar, Sims, Mark, Patel, Manish, Aziz, Qadeer, Ojake, Leona et al (show 7 more authors) (2024) Identification and characterisation of functional Kir6.1-containing ATP-sensitive potassium channels in the cardiac ventricular sarcolemmal membrane. British Journal of Pharmacology.

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Abstract

Background and purpose: The canonical Kir6.2/SUR2A ventricular KATP 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 shorten the action potential to reduce contractile activity. Pharmacological activation of KATP 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 KATP channel population could help explain this. Here, we characterise the biophysical and pharmacological behaviour of a constitutively-active Kir6.1-containing KATP 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 Kir6.1-containing channels. These Kir6.1-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 KATP channels: constitutively-active Kir6.1-containing channels that play an important role in fine-tuning the action potential; and Kir6.2/SUR2A channels that activate with prolonged ischaemia to impart late-stage protection against catastrophic ATP depletion. Further research is required to determine whether Kir6.1 is an overlooked target in Comprehensive in vitro Proarrhythmia Assay (CiPA) cardiac safety screens.

Item Type:	Article
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Depositing User:	Symplectic Admin
Date Deposited:	24 Apr 2024 08:08
Last Modified:	24 Apr 2024 08:08
DOI:	10.1111/bph.16390
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3180547