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Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways

Author

Listed:
  • Yulong Gong

    (Vanderbilt University
    Institute of Hydrobiology, Chinese Academy of Sciences)

  • Bingyuan Yang

    (Vanderbilt University)

  • Dingdong Zhang

    (Vanderbilt University
    Nanjing Agricultural University)

  • Yue Zhang

    (Vanderbilt University)

  • Zihan Tang

    (Vanderbilt University)

  • Liu Yang

    (Vanderbilt University)

  • Katie C. Coate

    (Vanderbilt University Medical Center)

  • Linlin Yin

    (Vanderbilt University)

  • Brittney A. Covington

    (Vanderbilt University)

  • Ravi S. Patel

    (Vanderbilt University)

  • Walter A. Siv

    (Vanderbilt University Medical Center)

  • Katelyn Sellick

    (Vanderbilt University Medical Center)

  • Matthew Shou

    (Vanderbilt University Medical Center)

  • Wenhan Chang

    (University of California San Francisco and San Francisco VA Medical Center)

  • E. Danielle Dean

    (Vanderbilt University
    Vanderbilt University Medical Center)

  • Alvin C. Powers

    (Vanderbilt University
    Vanderbilt University Medical Center
    VA Tennessee Valley Healthcare System)

  • Wenbiao Chen

    (Vanderbilt University)

Abstract

Glucagon has emerged as a key regulator of extracellular amino acid (AA) homeostasis. Insufficient glucagon signaling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Aside from mammalian target of rapamycin complex 1 (mTORC1), the role of other AA sensors in α cell proliferation has not been described. Here, using both genders of mouse islets and glucagon receptor (gcgr)-deficient zebrafish (Danio rerio), we show α cell proliferation requires activation of the extracellular signal-regulated protein kinase (ERK1/2) by the AA-sensitive calcium sensing receptor (CaSR). Inactivation of CaSR dampened α cell proliferation, which was rescued by re-expression of CaSR or activation of Gq, but not Gi, signaling in α cells. CaSR was also unexpectedly necessary for mTORC1 activation in α cells. Furthermore, coactivation of Gq and mTORC1 induced α cell proliferation independent of hyperaminoacidemia. These results reveal another AA-sensitive mediator and identify pathways necessary and sufficient for hyperaminoacidemia-induced α cell proliferation.

Suggested Citation

  • Yulong Gong & Bingyuan Yang & Dingdong Zhang & Yue Zhang & Zihan Tang & Liu Yang & Katie C. Coate & Linlin Yin & Brittney A. Covington & Ravi S. Patel & Walter A. Siv & Katelyn Sellick & Matthew Shou , 2023. "Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-022-35705-4
    DOI: 10.1038/s41467-022-35705-4
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    1. Manuel Grundmann & Nicole Merten & Davide Malfacini & Asuka Inoue & Philip Preis & Katharina Simon & Nelly Rüttiger & Nicole Ziegler & Tobias Benkel & Nina Katharina Schmitt & Satoru Ishida & Ines Mül, 2018. "Lack of beta-arrestin signaling in the absence of active G proteins," Nature Communications, Nature, vol. 9(1), pages 1-16, December.
    2. Patricia P. Centeno & Amanda Herberger & Hee-Chang Mun & Chialing Tu & Edward F. Nemeth & Wenhan Chang & Arthur D. Conigrave & Donald T. Ward, 2019. "Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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