Department of Physiology, University of Bern, Buehlplatz 5, CH-3012, Bern, Switzerland.
J Physiol. 2018 Sep;596(18):4323-4340. doi: 10.1113/JP276319. Epub 2018 Aug 7.
Augmented inositol 1,4,5-trisphosphate (IP ) receptor (IP R2) expression has been linked to a variety of cardiac pathologies. Although cardiac IP R2 function has been in the focus of research for some time, a detailed understanding of its potential role in ventricular myocyte excitation-contraction coupling under pathophysiological conditions remains elusive. The present study focuses on mechanisms of IP R2-mediated sarcoplasmic reticulum (SR)-Ca release in ventricular excitation-contraction coupling under IP R2-overexpressing conditions by studying intracellular Ca events. We report that, upon IP R2 overexpression in ventricular myocytes, IP -induced Ca release (IP ICR) modulates the SR-Ca content via "eventless" SR-Ca release, affecting the global SR-Ca leak. Thus, IP R2 activation could act as a SR-Ca gateway mechanism to escape ominous SR-Ca overload. Our approach unmasks a so far unrecognized mechanism by which "eventless" IP ICR plays a protective role against ventricular Ca -dependent arrhythmogenicity.
Augmented inositol 1,4,5-trisphosphate (IP ) receptor (IP R2) function has been linked to a variety of cardiac pathologies including cardiac arrhythmias. The functional role of IP -induced Ca release (IP ICR) within ventricular excitation-contraction coupling (ECC) remains elusive. As part of pathophysiological cellular remodelling, IP R2s are overexpressed and have been repeatedly linked to enhanced Ca -dependent arrhythmogenicity. In this study we test the hypothesis that an opposite scenario might be plausible in which IP ICR is part of an ECC protecting mechanism, resulting in a Ca -dependent anti-arrhythmogenic response on the cellular scale. IP R2 activation was triggered via endothelin-1 or IP -salt application in single ventricular myocytes from a cardiac-specific IP R type 2 overexpressing mouse model. Upon IP R2 overexpression, IP R activation reduced Ca -wave occurrence (46 vs. 21.72%; P < 0.001) while its block increased SR-Ca content (∼29.4% 2-aminoethoxydiphenyl borate, ∼16.4% xestospongin C; P < 0.001), suggesting an active role of IP ICR in SR-Ca content regulation and anti-arrhythmogenic function. Pharmacological separation of ryanodine receptor RyR2 and IP R2 functions and two-dimensional Ca event analysis failed to identify local IP ICR events (Ca puffs). SR-Ca leak measurements revealed that under pathophysiological conditions, "eventless" SR-Ca efflux via enhanced IP ICR maintains the SR-Ca content below Ca spark threshold, preventing aberrant SR-Ca release and resulting in a protective mechanism against SR-Ca overload and arrhythmias. Our results support a so far unrecognized modulatory mechanism in ventricular myocytes working in an anti-arrhythmogenic fashion.
已发现增强的肌醇 1,4,5-三磷酸（IP ）受体（IP R2）表达与多种心脏病理有关。尽管 IP R2 的心脏功能已成为研究的焦点一段时间，但在病理生理条件下，它在心室肌细胞兴奋-收缩偶联中的潜在作用仍难以捉摸。本研究通过研究细胞内 Ca 事件，着重研究 IP R2 过表达情况下 IP R2 介导的肌浆网（SR）-Ca 释放的机制在心室兴奋-收缩偶联中的作用。我们报告说，在心室肌细胞中过表达 IP R2 后，IP 诱导的 Ca 释放（IP ICR）通过“无事件”的 SR-Ca 释放调节 SR-Ca 含量，从而影响整体 SR-Ca 渗漏。因此，IP R2 的激活可以作为 SR-Ca 门控机制，以避免严重的 SR-Ca 过载。我们的方法揭示了一种迄今为止尚未被认识的机制，即“无事件”的 IP ICR 在对抗心室 Ca 依赖性心律失常方面发挥保护作用。
增强的肌醇 1,4,5-三磷酸（IP ）受体（IP R2）功能与多种心脏病理有关，包括心律失常。IP 诱导的 Ca 释放（IP ICR）在心室兴奋-收缩偶联（ECC）中的功能作用仍不清楚。作为病理生理细胞重塑的一部分，IP R2s 过表达并与增强的 Ca 依赖性心律失常性反复相关联。在这项研究中，我们检验了以下假设，即在相反的情况下，IP ICR 可能是 ECC 保护机制的一部分，从而在细胞水平上产生 Ca 依赖性抗心律失常反应。通过内皮素-1或 IP 盐在心脏特异性 IP R2 过表达小鼠模型的单个心室肌细胞中触发 IP R2 激活。在 IP R2 过表达后，IP R 激活减少了 Ca 波的发生（46 对 21.72％; P <0.001），而其阻断增加了 SR-Ca 含量（约 29.4％的 2-氨基乙氧基二苯硼酸，约 16.4％的 xestospongin C; P <0.001），这表明 IP ICR 在 SR-Ca 含量调节和抗心律失常功能中起积极作用。Ryanodine 受体 RyR2 和 IP R2 功能的药理学分离以及二维 Ca 事件分析未能识别局部 IP ICR 事件（Ca 气）。SR-Ca 泄漏测量显示，在病理生理条件下，通过增强的 IP ICR 的“无事件”SR-Ca 流出维持 SR-Ca 含量低于 Ca 火花阈值，防止异常的 SR-Ca 释放，并导致防止 SR-Ca 过载和心律失常的保护机制。我们的结果支持在心室肌细胞中以抗心律失常方式起作用的一种迄今为止尚未被认识的调节机制。
