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Nat Commun ; 14(1): 235, 2023 01 16.
Article in English | MEDLINE | ID: mdl-36646689

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.


Subject(s)
Glucagon-Secreting Cells , Mechanistic Target of Rapamycin Complex 1 , Receptors, Calcium-Sensing , Signal Transduction , Animals , Female , Male , Mice , Calcium/metabolism , Cell Proliferation , Glucagon , Glucagon-Secreting Cells/metabolism , Receptors, Calcium-Sensing/metabolism , Zebrafish/metabolism , Mechanistic Target of Rapamycin Complex 1/metabolism
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