1. Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways.
- Author
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Gong Y, Yang B, Zhang D, Zhang Y, Tang Z, Yang L, Coate KC, Yin L, Covington BA, Patel RS, Siv WA, Sellick K, Shou M, Chang W, Danielle Dean E, Powers AC, and Chen W
- Subjects
- Animals, Female, Male, Mice, Calcium metabolism, Cell Proliferation, Glucagon, Zebrafish metabolism, Glucagon-Secreting Cells metabolism, Receptors, Calcium-Sensing metabolism, Signal Transduction, Mechanistic Target of Rapamycin Complex 1 metabolism
- 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., (© 2023. The Author(s).)
- Published
- 2023
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