| First Author | Zhu S | Year | 2022 |
| Journal | Nat Commun | Volume | 13 |
| Issue | 1 | Pages | 4278 |
| PubMed ID | 35879328 | Mgi Jnum | J:379831 |
| Mgi Id | MGI:7326585 | Doi | 10.1038/s41467-022-31992-z |
| Citation | Zhu S, et al. (2022) The RalGAPalpha1-RalA signal module protects cardiac function through regulating calcium homeostasis. Nat Commun 13(1):4278 |
| abstractText | 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 RalGAPalpha1 as a critical regulator of SERCA2 in cardiomyocytes through its downstream target RalA. RalGAPalpha1 is induced by pressure overload, and its deficiency causes cardiac dysfunction and exacerbates pressure overload-induced heart failure. Mechanistically, RalGAPalpha1 regulates SERCA2 through direct interaction and its target RalA. Deletion of RalGAPalpha1 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. |
