Does the small conductance Ca2+-activated K+ current ISK flow under physiological conditions in rabbit and human atrial isolated cardiomyocytes?

Giommi, A., Gurgel, A. R. B., Smith, G. L. and Workman, A. J. (2023) Does the small conductance Ca2+-activated K+ current ISK flow under physiological conditions in rabbit and human atrial isolated cardiomyocytes? Journal of Molecular and Cellular Cardiology, 183, pp. 70-80. (doi: 10.1016/j.yjmcc.2023.09.002) (PMID:37704101)

Abstract

Background: The small conductance Ca2+-activated K+ current (ISK) is a potential therapeutic target for treating atrial fibrillation. Aim: To clarify, in rabbit and human atrial cardiomyocytes, the intracellular [Ca2+]-sensitivity of ISK, and its contribution to action potential (AP) repolarisation, under physiological conditions. Methods: Whole-cell-patch clamp, fluorescence microscopy: to record ion currents, APs and [Ca2+]i; 35–37°C. Results: In rabbit atrial myocytes, 0.5 mM Ba2+ (positive control) significantly decreased whole-cell current, from −12.8 to −4.9 pA/pF (P < 0.05, n = 17 cells, 8 rabbits). By contrast, the ISK blocker apamin (100 nM) had no effect on whole-cell current, at any set [Ca2+]i (~100–450 nM). The ISK blocker ICAGEN (1 μM: ≥2 x IC50) also had no effect on current over this [Ca2+]i range. In human atrial myocytes, neither 1 μM ICAGEN (at [Ca2+]i ~ 100–450 nM), nor 100 nM apamin ([Ca2+]i ~ 250 nM) affected whole-cell current (5–10 cells, 3–5 patients/group). APs were significantly prolonged (at APD30 and APD70) by 2 mM 4-aminopyridine (positive control) in rabbit atrial myocytes, but 1 μM ICAGEN had no effect on APDs, versus either pre-ICAGEN or time-matched controls. High concentration (10 μM) ICAGEN (potentially ISK-non-selective) moderately increased APD70 and APD90, by 5 and 26 ms, respectively. In human atrial myocytes, 1 μM ICAGEN had no effect on APD30–90, whether stimulated at 1, 2 or 3 Hz (6–9 cells, 2–4 patients/rate). Conclusion: ISK does not flow in human or rabbit atrial cardiomyocytes with [Ca2+]i set within the global average diastolic-systolic range, nor during APs stimulated at physiological or supra-physiological (≤3 Hz) rates.

• Item Type: Articles
• Additional Information: This work was supported by the “EU Training network on novel targets and methods in atrial fibrillation” (AFib-TrainNet), ID: 675351.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Workman, Dr Antony and Smith, Professor Godfrey and Giommi, Alessandro
• Authors: Giommi, A., Gurgel, A. R. B., Smith, G. L., and Workman, A. J.
• College/School: College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
• Journal Name: Journal of Molecular and Cellular Cardiology
• Publisher: Elsevier
• ISSN: 0022-2828
• ISSN (Online): 1095-8584
• Published Online: 12 September 2023
• Copyright Holders: Copyright © 2023 The Authors
• First Published: First published in Journal of Molecular and Cellular Cardiology 183:70-80
• Publisher Policy: Reproduced under a Creative Commons license

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
172294		Afib-TrainNet	Godfrey Smith	European Commission (EC)	675351	School of Cardiovascular & Metabolic Health