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

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  • 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)

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.

Suggested Citation

  • 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 & Shuai Chen, 2022. "The RalGAPα1–RalA signal module protects cardiac function through regulating calcium homeostasis," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31992-z
    DOI: 10.1038/s41467-022-31992-z
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    References listed on IDEAS

    as
    1. Changwon Kho & Ahyoung Lee & Dongtak Jeong & Jae Gyun Oh & Antoine H. Chaanine & Eddy Kizana & Woo Jin Park & Roger J. Hajjar, 2011. "SUMO1-dependent modulation of SERCA2a in heart failure," Nature, Nature, vol. 477(7366), pages 601-605, September.
    2. Changwon Kho & Ahyoung Lee & Dongtak Jeong & Jae Gyun Oh & Przemek A. Gorski & Kenneth Fish & Roberto Sanchez & Robert J. DeVita & Geir Christensen & Russell Dahl & Roger J. Hajjar, 2015. "Small-molecule activation of SERCA2a SUMOylation for the treatment of heart failure," Nature Communications, Nature, vol. 6(1), pages 1-11, November.
    3. Chao Quan & Qian Du & Min Li & Ruizhen Wang & Qian Ouyang & Shu Su & Sangsang Zhu & Qiaoli Chen & Yang Sheng & Liang Chen & Hong Wang & David G. Campbell & Carol MacKintosh & Zhongzhou Yang & Kunfu Ou, 2020. "A PKB-SPEG signaling nexus links insulin resistance with diabetic cardiomyopathy by regulating calcium homeostasis," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
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