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

Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing alpha cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for alpha cell proliferation via Gq signalling during hyperaminoacidemia. 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 alpha cells. Aside from mammalian target of rapamycin complex 1 (mTORC1), the role of other AA sensors in alpha cell proliferation has not been described. Here, using both genders of mouse islets and glucagon receptor (gcgr)-deficient zebrafish (Danio rerio), we show alpha 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 alpha cell proliferation, which was rescued by re-expression of CaSR or activation of Gq, but not Gi, signaling in alpha cells. CaSR was also unexpectedly necessary for mTORC1 activation in alpha cells. Furthermore, coactivation of Gq and mTORC1 induced alpha cell proliferation independent of hyperaminoacidemia. These results reveal another AA-sensitive mediator and identify pathways necessary and sufficient for hyperaminoacidemia-induced alpha cell proliferation.