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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.
Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.
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1 Vanderbilt University, Department of Molecular Physiology & Biophysics, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217); Institute of Hydrobiology, Chinese Academy of Sciences, State Key Laboratory of Freshwater Ecology and Biotechnology, Wuhan, China (GRID:grid.429211.d) (ISNI:0000 0004 1792 6029)
2 Vanderbilt University, Department of Molecular Physiology & Biophysics, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217)
3 Vanderbilt University, Department of Molecular Physiology & Biophysics, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217); Nanjing Agricultural University, College of Animal Science and Technology, Nanjing, China (GRID:grid.27871.3b) (ISNI:0000 0000 9750 7019)
4 Vanderbilt University Medical Center, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916)
5 University of California San Francisco and San Francisco VA Medical Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811)
6 Vanderbilt University, Department of Molecular Physiology & Biophysics, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217); Vanderbilt University Medical Center, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916)
7 Vanderbilt University, Department of Molecular Physiology & Biophysics, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217); Vanderbilt University Medical Center, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916); VA Tennessee Valley Healthcare System, Nashville, USA (GRID:grid.452900.a) (ISNI:0000 0004 0420 4633)