PUBLICATION

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

Authors

Gong, Y., Yang, B., Zhang, D., Zhang, Y., Tang, Z., Yang, L., Coate, K.C., Yin, L., Covington, B.A., Patel, R.S., Siv, W.A., Sellick, K., Shou, M., Chang, W., Danielle Dean, E., Powers, A.C., Chen, W.

ID

ZDB-PUB-230117-12

Date

2023

Source

Nature communications 14: 235235 (Journal)

Registered Authors

Chen, Wenbiao

Keywords

none

MeSH Terms

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

(all 12)

PubMed

36646689 Full text @ Nat. Commun.

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.

Genes / Markers

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