The RalGAPα1-RalA signal module protects cardiac function through regulating calcium homeostasis.
The RalGAPα1-RalA signal module protects cardiac function through regulating calcium homeostasis.
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DOI：
10.1038/s41467-022-31992-z
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发表时间：
2022-07-25
影响因子：
16.6
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肌质/内质网钙ATP酶SERCA 2介导钙从胞质溶胶再摄取到肌质网中，并且其功能障碍是心力衰竭的标志。已经确定了多种因素来调节SERCA 2活性，然而，其调节仍然没有完全理解。在这里，我们确定了一个Ral-GT3激活蛋白RalGAPα1作为心肌细胞中SERCA 2的关键调节因子，通过其下游靶点RalA。RalGAPα1由压力超负荷诱导，其缺乏会导致心功能不全并加重压力超负荷诱导的心力衰竭。从机制上讲，RalGAPα1通过直接相互作用及其靶标RalA调节SERCA 2。RalGAPα1的缺失降低了SERCA 2活性和肌浆网中钙的再摄取。GDP结合的RalA，而不是GTP结合的RalA，与SERCA 2结合并激活肌浆网钙再摄取的泵。心脏中GDP结合的RalAS 28 N突变体的过表达保留了心力衰竭小鼠模型的心脏功能。我们的研究结果对心力衰竭的治疗具有治疗意义。在这里，作者表明RalGAPα1-RalA信号联系通过钙泵SERCA 2a调节心肌细胞中的钙稳态，这在压力超负荷条件下对维持心脏功能起保护作用。
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 RalAS28N mutant in the heart preserves cardiac function in a mouse model of heart failure. Our findings have therapeutic implications for treatment of heart failure. Here the authors show that a RalGAPα1-RalA signal nexus regulates calcium homeostasis in cardiomyocytes via the calcium pump SERCA2a, which plays a protective role to maintain cardiac function under pressure overload conditions.
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影响因子：
64.8
作者：
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