Transient Receptor Potential Vanilloid 4 channel participates in mouse ventricular electrical activity

Abstract

Transient Receptor Potential Vanilloid 4 (TRPV4) channel is a calcium permeable channel (P Ca /P Na ∼ 10). Its expression was reported in ventricular myocytes where it is involved in several cardiac pathological mechanisms. In this study, we investigated the implication of TRPV4 in ventricular electrical activity. Left ventricular myocytes were isolated from trpv4 +/+ and trpv4 −/− mice. TRPV4 membrane expression and its colocalization with Ca v 1.2 was confirmed using western-blots biotinylation, immunoprecipitation and immunostaining experiments. Then, electrocardiograms (ECGs) and patch-clamp recordings showed shortened QTc and action potential (AP) duration in trpv4 −/− compared to trpv4 +/+ mice. Thus, TRPV4 activator GSK1016790A produced a transient and dose-dependent increase in AP duration at 90% of repolarization (APD 90 ) in trpv4 +/+ , but not in trpv4 −/− myocytes or when combined with TRPV4 inhibitor GSK2193874 (100 nM). Hence, GSK1016790A increased CaT amplitude in trpv4 +/+ but not in trpv4 −/− myocytes, suggesting that TRPV4 carries an inward Ca 2+ current in myocytes. Conversely, TRPV4 inhibitor GSK2193874 (100 nM) alone reduced APD 90 in trpv4 +/+ but not in trpv4 −/− myocytes, suggesting that TRPV4 prolongs AP duration (APD) in basal condition. Finally, introducing TRPV4 parameters in a mathematical model predicted the development of an inward TRPV4 current during repolarization that increases AP duration and CaT amplitude, in accordance with what found experimentally. This study shows for the first time that TRPV4 modulates AP and QTc durations. It would be interesting to evaluate whether TRPV4 could be involved in long QT-mediated ventricular arrhythmias.