Overexpression of the large‐conductance, Ca²⁺‐activated K⁺ (BK) channel shortens action potential duration in HL‐1 cardiomyocytes

Abstract

Hereditary long‐QT syndrome (LQTS) is caused by mutations in ion channel genes resulting in a prolonged action potential duration (APD) in cardiomyocytes. Complications include syncope and sudden cardiac death. Large‐conductance, Ca2+‐activated K+ (BK) channels mediate repolarization of many cell types, but they are not expressed in the plasma membrane of cardiomyocytes. We hypothesized that introduction of BK channels may shorten APD in cardiomyocytes as a potential therapy for LQTS. HL‐1 atrial myocytes were transiently transfected with BK plasmids bicistronically expressing hBK and mCherry or control plasmids expressing only mCherry. Expression of the hBK transgene was confirmed by Western blot, immunocytochemistry and by detecting iberiotoxin (Ibtx)‐sensitive BK current in patch‐clamped cells. Western blots showed that the expression of other ion channels including KV4.3, KV7.1, NaV1.5, and CaV1.2 did not significantly change after BK transfection, whereas KV11.1 was down‐regulated by 20% (n=5). APD at 50% repolarization was 3.7±0.5 ms in BK‐transfected cells compared to 6.3±0.6 ms in control‐transfected cells. Ibtx (100 nmol/L) restored the shortened APD in hBK‐transfected cells to 7.9±1.5 ms (n=5–14). Thus, BK channels can exert a powerful repolarizing influence in HL‐1 myocytes, and may be a useful therapy to reverse LQTS. AHA SDG 0830060N (SWR) and NIH R01HL093526 (NJR)