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
  • Zebrafish/metabolism
  • Glucagon
  • Animals
  • Male
  • Mice
  • Female
  • Receptors, Calcium-Sensing*/metabolism
  • Calcium/metabolism
  • Signal Transduction*
  • Cell Proliferation
  • Mechanistic Target of Rapamycin Complex 1*/metabolism
  • Glucagon-Secreting Cells*/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
Figures
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
ia1TgTransgenic Insertion
    vu708
      		Small Deletion
      vu709
        		Indel
        vu710TgTransgenic Insertion
          vu711TgTransgenic Insertion
            vu712TgTransgenic Insertion
              vu713TgTransgenic Insertion
                vu714TgTransgenic Insertion
                  1 - 8 of 8
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  Target Reagent Reagent Type
                  casrCRISPR2-casrCRISPR
                  1 - 1 of 1
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                  Fish
                  No data available
                  Antibodies
                  Orthology
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  GFPEFGGFP
                  hM3DqEFGmodified human M3 muscarinic (hM3) receptor
                  hM4DiEFGhM4Di
                  TagRFPEFGTagRFP
                  YFPEFGYFP
                  1 - 5 of 5
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                  Mapping
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                  Citation
                  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. (2023) Hyperaminoacidemia induces pancreatic α cell proliferation via synergism between the mTORC1 and CaSR-Gq signaling pathways. Nature communications. 14:235235.