心肌细胞横管-肌质网耦联与钙信号调控  

Couplons between transverse tubules and sarcoplasmic reticulum:roles in calcium signaling

作　　者：邢昕 梁景辉 王世强[1] XING Xin;LIANG JingHui;WANG ShiQiang(State Key Laboratory of Membrane Biology,College of Life Sciences,Peking University,Beijing 100871,China)

机构地区：[1]北京大学生命科学学院膜生物学国家重点实验室,北京100871

出　　处：《中国科学：生命科学》2022年第1期5-16,共12页Scientia Sinica(Vitae)

基　　金：国家自然科学基金(批准号:91854209,31630035)资助。

摘　　要：心肌细胞的兴奋沿横管传入细胞深处并激活L型钙通道,进而通过钙致钙释放机制激活肌质网ryanodine受体钙释放通道,由此产生的钙火花叠加成为细胞钙瞬变,引发心肌细胞同步化收缩.β;型肾上腺素受体介导的广域cAMP信号通过磷酸化L型钙通道、ryanodine受体、肌质网受磷蛋白,分别上调钙内流、钙释放和肌质网钙泵的钙回收速率,从而增强心脏泵血能力.β;型肾上腺素受体一方面通过局域cAMP信号磷酸化L型钙通道,另一方面通过G蛋白耦联受体激酶-2介导的"越位阻隔"抑制β;受体对肌质网钙释放和钙回收的调控.心力衰竭病理过程中,由于铆定横管与肌质网的junctophilin-2下调,横管与肌质网发生结构和功能脱耦联,造成心脏泵血能力低下冬眠动物能通过转录因子myocardin上调junctophilin-2和caveolin-3,增强横管与肌质网的结构和功能耦联,从而保证冬眠状态下的心脏泵血能力.进一步探明横管与肌质网间钙致钙释放稳态调控的分子机制将为有关心脏疾病的防治提供新思路.In cardiomyocytes,the excitation signal propagates along transverse tubules (TTs) and excits L-type calcium channels (LCCs),which in turn activate ryanodine receptor (RyR) calcium release from the sarcoplasmic reticulum (SR) via the calcium-induced calcium release (CICR) mechanism.This process induces calcium sparks,which sum up into a calcium transient that drives synchronized heart cell contraction.The global signaling ofβ;adrenergic receptors,by phosphorylating LCCs,RyRs and phospholamban,upregulates calcium influx,release and uptake,and enhances blood pumping power.In contrast,β;adrenoceptors mediate local cAMP signaling that phosphorylates LCCs,but keepβ;receptors from regulating calcium release/uptake via an“offside compartmentalization”mechanism mediated by G-protein coupled receptor kinase.During heart failure,the down-regulation of junctophilin-2 (JPH2) uncouples TTs and SRs,leading to compromised blood pumping power.During hibernation,however,the concerted up-regulation of JPH2 and caveolin-3 tightens TT-SR coupons,and enhances myocardial pumping capacity.Further exploration of the molecular mechanisms that regulate the CICR between LCCs and Ry Rs will provide new ideas for treating heart diseases.

关 键 词：横管 肌质网 钙信号 Β肾上腺素受体 心力衰竭 冬眠 

分 类 号：R331.31[医药卫生—人体生理学]