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

Sangsang Zhu, Chao Quan, Ruizhen Wang, Derong Liang, Shu Su, Ping Rong, Kun Zhou, Xinyu Yang, Qiaoli Chen, Min Li, Qian Du, Jingzi Zhang, Lei Fang, Hong-Yu Wang () and Shuai Chen ()
Additional contact information
Sangsang Zhu: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Chao Quan: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Ruizhen Wang: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Derong Liang: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Shu Su: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Ping Rong: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Kun Zhou: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Xinyu Yang: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Qiaoli Chen: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Min Li: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Qian Du: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Jingzi Zhang: Nanjing University
Lei Fang: Nanjing University
Hong-Yu Wang: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University
Shuai Chen: The Affiliated Hospital of Nanjing University Medical School, Model Animal Research Center, Nanjing University

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-31992-z

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