PDF(Pubmed)
Abstract：
The contraction of heart cells is controlled by the intermolecular signaling between L-type Ca2+ channels (LCCs) and ryanodine receptors (RyRs), and the nanodistance between them depends on the interaction between junctophilin-2 (JPH2) in the sarcoplasmic reticulum (SR) and caveolin-3 (CAV3) in the transversal tubule (TT). In heart failure, decreased expression of JPH2 compromises LCC-RyR communication leading to deficient blood-pumping power. In the present study, we found that JPH2 and CAV3 transcription was concurrently regulated by serum response factor (SRF) and myocardin. In cardiomyocytes from torpid ground squirrels, compared with those from euthermic counterparts, myocardin expression was up-regulated, which boosted both JPH2 and CAV3 expression. Transmission electron microscopic imaging showed that the physical coupling between TTs and SRs was tightened during hibernation and after myocardin overexpression. Confocal Ca2+ imaging under the whole-cell patch clamp condition revealed that these changes enhanced the efficiency of LCC-RyR intermolecular signaling and fully compensated the adaptive down-regulation of LCCs, maintaining the power of heart contraction while avoiding the risk of calcium overload during hibernation. Our finding not only revealed an essential molecular mechanism underlying the survival of hibernating mammals, but also demonstrated a \"reverse model of heart failure\" at the molecular level, suggesting a strategy for treating heart diseases.
摘要：
心脏细胞的收缩受L型Ca2+通道(LCCs)和ryanodine受体(RyRs)之间的分子间信号传导控制,它们之间的纳米距离取决于肌浆网（SR）中的junctophilin-2（JPH2）与横管（TT）中的caveolin-3（CAV3）之间的相互作用。在心力衰竭中，JPH2表达降低会损害LCC-RyR通讯，导致抽血能力不足。在本研究中,我们发现JPH2和CAV3转录同时受血清反应因子（SRF）和心肌素调节。在来自硬松鼠的心肌细胞中，与优热同行相比，myocardin表达上调，这促进了JPH2和CAV3的表达。透射电子显微镜成像显示，在冬眠期间和myocardin过表达后，TT和SRs之间的物理耦合增强。全细胞膜片钳条件下共焦Ca2+成像显示这些变化增强了LCC-RyR分子间信号传导的效率，完全补偿了LCC的适应性下调，保持心脏收缩的力量，同时避免冬眠期间钙超载的风险。我们的发现不仅揭示了冬眠哺乳动物生存的基本分子机制，而且还在分子水平上展示了一个“心力衰竭逆转模型”，建议一种治疗心脏病的策略.
