State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University, Nanjing, China.
School of Medicine, Nanjing University, Nanjing, China.
Nat Commun. 2022 Jul 25;13(1):4278. doi: 10.1038/s41467-022-31992-z.
Sarcoplasmic/endoplasmic reticulum calcium ATPase SERCA2 mediates calcium re-uptake from the cytosol into sarcoplasmic reticulum, and its dysfunction is a hallmark of heart failure. Multiple factors have been identified to modulate SERCA2 activity, however, its regulation is still not fully understood. Here we identify a Ral-GTPase activating protein RalGAPα1 as a critical regulator of SERCA2 in cardiomyocytes through its downstream target RalA. RalGAPα1 is induced by pressure overload, and its deficiency causes cardiac dysfunction and exacerbates pressure overload-induced heart failure. Mechanistically, RalGAPα1 regulates SERCA2 through direct interaction and its target RalA. Deletion of RalGAPα1 decreases SERCA2 activity and prolongs calcium re-uptake into sarcoplasmic reticulum. GDP-bound RalA, but not GTP-bound RalA, binds to SERCA2 and activates the pump for sarcoplasmic reticulum calcium re-uptake. Overexpression of a GDP-bound RalA mutant in the heart preserves cardiac function in a mouse model of heart failure. Our findings have therapeutic implications for treatment of heart failure.
肌浆网/内质网钙 ATP 酶 SERCA2 将细胞质中的钙重新摄取到肌浆网中，其功能障碍是心力衰竭的一个标志。已经确定了多种因素来调节 SERCA2 的活性，但其调节机制仍不完全清楚。在这里，我们通过其下游靶标 RalA 鉴定出一种 Ral-GTP 酶激活蛋白 RalGAPα1 是心肌细胞中 SERCA2 的关键调节因子。RalGAPα1 受压力超负荷诱导，其缺失导致心脏功能障碍并加重压力超负荷诱导的心力衰竭。在机制上，RalGAPα1 通过直接相互作用及其靶标 RalA 来调节 SERCA2。RalGAPα1 的缺失会降低 SERCA2 的活性并延长钙重新摄取到肌浆网中。GDP 结合的 RalA，而不是 GTP 结合的 RalA，与 SERCA2 结合并激活肌浆网钙摄取泵。在心力衰竭的小鼠模型中，心脏过表达 GDP 结合的 RalA 突变体可保留心脏功能。我们的发现为心力衰竭的治疗提供了治疗意义。
