The RalGAPα1-RalA signal module protects cardiac function through regulating calcium homeostasis

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 RalGAP alpha 1 as a critical regulator of SERCA2 in cardiomyocytes through its downstream target RalA. RalGAP alpha 1 is induced by pressure overload, and its deficiency causes cardiac dysfunction and exacerbates pressure overload-induced heart failure. Mechanistically, RalGAP alpha 1 regulates SERCA2 through direct interaction and its target RalA. Deletion of RalGAP alpha 1 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(S28N) 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 RalGAP alpha 1-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.

Automated summary

RalGAP alpha 1-RalA signal nexus plays a key role in regulating calcium homeostasis in cardiomyocytes through the calcium pump SERCA2a, which helps maintain cardiac function under pressure overload conditions.