Introduction: 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. Methods and Results: Left ventricular myocytes were isolated from trpv4^+/+and trpv4^-/- mice. TRPV4 membrane expression and its colocalization with Ca_v1.2 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 intrpv4^-/- compared to trpv4^+/+ mice. Thus, TRPV4 activator GSK1016790A produced a transient and dose-dependent increase in AP duration at 90 % of repolarization (APD₉₀) 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 Ca²⁺ current in myocytes. Conversely, TRPV4 inhibitor GSK2193874 (100 nM) alone reduced APD₉₀ 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. Conclusion: This study shows for the first time that TRPV4 modulates AP and QTc durations and constitutes thereby a good therapeutical target against long QT-mediated ventricular arrhythmias. Keywords: TRPV4 channel, action potential, QT interval, mathematical modeling, trpv4^-/-, calcium transient.

中文翻译：

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瞬态受体电位香草酸4通道参与小鼠心室电活动

介绍：瞬时受体电位香草酸4（TRPV4）信道是钙可渗透通道（P_钙/ P_钠〜10）。据报道它的表达在心室肌细胞中，它参与了几种心脏病理机制。在这项研究中，我们调查了TRPV4对心室电活动的影响。方法和结果：从trpv4 ^{+ / +}中分离出左心室心肌细胞和trpv4 ^-/-小鼠。使用western-blots生物素化，免疫沉淀和免疫染色实验证实了TRPV4膜的表达及其与Ca _v 1.2的共定位。然后，心电图（ECG）和膜片钳记录显示缩短了QTc和动作电位（AP）持续时间。trpv4 ^-/-与trpv4 ^{+ / +}小鼠相比。因此，TRPV4激活剂GSK1016790A在trpv4 ^{+ / +}的复极化（APD ₉₀）的90％时，AP持续时间短暂而剂量依赖性地增加，但在trpv4 ^-/-心肌细胞中或与TRPV4抑制剂GSK2193874（100 nM）结合时，不会持续。因此，GSK1016790A增加了trpv4 ^{+ / +中的}CaT幅度但在trpv4 ^-/-心肌细胞中却没有，这表明TRPV4在心肌细胞中携带内向Ca ²⁺电流。相反，仅TRPV4抑制剂GSK2193874（100 nM）会降低trpv4 ^{+ / +中的}APD ₉₀但在trpv4 ^-/-心肌细胞中却没有，这表明在基础状态下TRPV4延长了AP持续时间（APD）。最后，根据实验发现，在数学模型中引入TRPV4参数可预测复极化期间内向TRPV4电流的发展，这会增加AP持续时间和CaT幅度。结论：本研究首次显示TRPV4调节AP和QTc持续时间，从而构成针对长QT介导的室性心律失常的良好治疗靶标。关键字：TRPV4通道，动作电位，QT间隔，数学模型，trpv4 ^-/-，钙瞬变。