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.

Details

Title
Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways
Author
Gong, Yulong 1 ; Yang, Bingyuan 2 ; Zhang, Dingdong 3   VIAFID ORCID Logo  ; Zhang, Yue 2 ; Tang, Zihan 2 ; Yang, Liu 2 ; Coate, Katie C. 4   VIAFID ORCID Logo  ; Yin, Linlin 2 ; Covington, Brittney A. 2 ; Patel, Ravi S. 2 ; Siv, Walter A. 4 ; Sellick, Katelyn 4 ; Shou, Matthew 4 ; Chang, Wenhan 5   VIAFID ORCID Logo  ; Danielle Dean, E. 6 ; Powers, Alvin C. 7 ; Chen, Wenbiao 2   VIAFID ORCID Logo 

 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) 
 Vanderbilt University, Department of Molecular Physiology & Biophysics, Nashville, USA (GRID:grid.152326.1) (ISNI:0000 0001 2264 7217) 
 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) 
 Vanderbilt University Medical Center, Division of Diabetes, Endocrinology and Metabolism, Department of Medicine, Nashville, USA (GRID:grid.412807.8) (ISNI:0000 0004 1936 9916) 
 University of California San Francisco and San Francisco VA Medical Center, San Francisco, USA (GRID:grid.266102.1) (ISNI:0000 0001 2297 6811) 
 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) 
 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) 
Pages
235
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2765886896
Copyright
© The Author(s) 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.