Instituts hospitalo-universitaires, L'Institut de Rythmologie et Modélisation Cardiaque, Fondation Bordeaux Université, Bordeaux, France.
Electrophysiology and Ablation Unit, Bordeaux University Hospital, Pessac, France.
Am J Physiol Heart Circ Physiol. 2021 Mar 1;320(3):H1156-H1169. doi: 10.1152/ajpheart.00497.2020. Epub 2021 Jan 15.
The TRPV4 channel is a calcium-permeable channel (/ ∼ 10). Its expression has been 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 and mice. TRPV4 membrane expression and its colocalization with L-type calcium channels (Ca1.2) was confirmed using Western blot biotinylation, immunoprecipitation, and immunostaining experiments. Then, electrocardiograms (ECGs) and patch-clamp recordings showed shortened QTc and action potential (AP) duration in compared with mice. Thus, TRPV4 activator GSK1016790A produced a transient and dose-dependent increase in AP duration at 90% of repolarization (APD) in but not in myocytes or when combined with TRPV4 inhibitor GSK2193874 (100 nM). Hence, GSK1016790A increased calcium transient (CaT) amplitude in but not in myocytes, suggesting that TRPV4 carries an inward Ca current in myocytes. Conversely, TRPV4 inhibitor GSK2193874 (100 nM) alone reduced APD in but not in myocytes, suggesting that TRPV4 prolongs AP duration 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 accord with what was 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. Transient receptor potential vanilloid 4 (TRPV4) is expressed at the membrane of mouse ventricular myocytes and colocalizes with non-T-tubular L-type calcium channels. Deletion of trpv4 gene in mice results in shortened QT interval on electrocardiogram and reduced action potential duration of ventricular myocytes. Pharmacological activation of TRPV4 channel leads to increased action potential duration and increased calcium transient amplitude in but not in ventricular myocytes. To the contrary, TRPV4 channel pharmacological inhibition reduces action potential duration in but not in myocytes. Integration of TRPV4 channel in a computational model of mouse action potential shows that the channel carries an inward current contributing to slowing down action potential repolarization and to increase calcium transient amplitude, similarly to what is observed experimentally. This study highlights for the first time the involvement of TRPV4 channel in ventricular electrical activity.
瞬时受体电位香草酸亚型 4（TRPV4）通道是一种钙通透性通道（/ ∼ 10）。其在心室肌细胞中的表达已被报道，在该细胞中，它参与了几种心脏病理机制。在这项研究中，我们研究了 TRPV4 在心室电活动中的作用。从小鼠的左心室心肌细胞中分离出来。使用 Western blot 生物素化、免疫沉淀和免疫染色实验证实了 TRPV4 膜表达及其与 L 型钙通道（Ca1.2）的共定位。然后，心电图（ECG）和膜片钳记录显示，与 相比， 小鼠的 QTc 和动作电位（AP）持续时间缩短。因此，TRPV4 激活剂 GSK1016790A 在 心肌细胞中产生短暂的、剂量依赖性的复极化 90%时程（APD）增加，而在 心肌细胞中则没有，或者与 TRPV4 抑制剂 GSK2193874（100 nM）联合使用时也没有。因此，GSK1016790A 增加了 心肌细胞中的钙瞬变（CaT）幅度，但在 心肌细胞中则没有，表明 TRPV4 在心肌细胞中携带内向钙电流。相反，TRPV4 抑制剂 GSK2193874（100 nM）单独降低了 心肌细胞中的 APD，但在 心肌细胞中则没有，表明 TRPV4 在基础条件下延长了 AP 持续时间。最后，在数学模型中引入 TRPV4 参数预测了在复极化过程中内向 TRPV4 电流的发展，该电流增加了 AP 持续时间和 CaT 幅度，与实验中发现的结果一致。这项研究首次表明 TRPV4 调节 AP 和 QTc 持续时间。评估 TRPV4 是否参与长 QT 介导的室性心律失常将是有趣的。瞬时受体电位香草酸亚型 4（TRPV4）在小鼠心室肌细胞膜上表达，并与非 T 管型 L 型钙通道共定位。在小鼠中删除 trpv4 基因导致心电图上 QT 间期缩短和心室肌细胞动作电位持续时间缩短。TRPV4 通道的药理学激活导致 但不是 心室肌细胞中的动作电位持续时间延长和钙瞬变幅度增加。相反，TRPV4 通道的药理学抑制减少了 但不是 心肌细胞中的动作电位持续时间。将 TRPV4 通道整合到小鼠动作电位的计算模型中表明，该通道携带内向电流，有助于减缓动作电位复极化并增加钙瞬变幅度，与实验观察到的结果相似。这项研究首次强调了 TRPV4 通道在心室电活动中的作用。
