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Progesterone receptor membrane component 1 is a functional part of the glucagon-like peptide-1 (GLP-1) receptor complex in pancreatic β cells.
- Source :
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Molecular & cellular proteomics : MCP [Mol Cell Proteomics] 2014 Nov; Vol. 13 (11), pp. 3049-62. Date of Electronic Publication: 2014 Jul 20. - Publication Year :
- 2014
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Abstract
- Glucagon-like peptide-1 (GLP-1) is an incretin hormone that regulates glucose homeostasis. Because of their direct stimulation of insulin secretion from pancreatic β cells, GLP-1 receptor (GLP-1R) agonists are now important therapeutic options for the treatment of type 2 diabetes. To better understand the mechanisms that control the insulinotropic actions of GLP-1, affinity purification and mass spectrometry (AP-MS) were employed to uncover potential proteins that functionally interact with the GLP-1R. AP-MS performed on Chinese hamster ovary cells or MIN6 β cells, both expressing the human GLP-1R, revealed 99 proteins potentially associated with the GLP-1R. Three novel GLP-1R interactors (PGRMC1, Rab5b, and Rab5c) were further validated through co-immunoprecipitation/immunoblotting, fluorescence resonance energy transfer, and immunofluorescence. Functional studies revealed that overexpression of PGRMC1, a novel cell surface receptor that associated with liganded GLP-1R, enhanced GLP-1-induced insulin secretion (GIIS) with the most robust effect. Knockdown of PGRMC1 in β cells decreased GIIS, indicative of positive interaction with GLP-1R. To gain insight mechanistically, we demonstrated that the cell surface PGRMC1 ligand P4-BSA increased GIIS, whereas its antagonist AG-205 decreased GIIS. It was then found that PGRMC1 increased GLP-1-induced cAMP accumulation. PGRMC1 activation and GIIS induced by P4-BSA could be blocked by inhibition of adenylyl cyclase/EPAC signaling or the EGF receptor-PI3K signal transduction pathway. These data reveal a dual mechanism for PGRMC1-increased GIIS mediated through cAMP and EGF receptor signaling. In conclusion, we identified several novel GLP-1R interacting proteins. PGRMC1 expressed on the cell surface of β cells was shown to interact with the activated GLP-1R to enhance the insulinotropic actions of GLP-1.<br /> (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)
- Subjects :
- Adenylyl Cyclase Inhibitors
Animals
CHO Cells
Cell Line
Cricetinae
Cricetulus
Cyclic AMP biosynthesis
Cyclic AMP metabolism
ErbB Receptors antagonists & inhibitors
ErbB Receptors metabolism
Glucagon-Like Peptide-1 Receptor
Guanine Nucleotide Exchange Factors antagonists & inhibitors
Guanine Nucleotide Exchange Factors metabolism
Humans
Insulin Secretion
Mass Spectrometry
Membrane Proteins antagonists & inhibitors
Membrane Proteins genetics
Mice
Phosphatidylinositol 3-Kinases metabolism
Phosphoinositide-3 Kinase Inhibitors
Rats
Receptors, Progesterone antagonists & inhibitors
Receptors, Progesterone genetics
rab5 GTP-Binding Proteins metabolism
Glucagon-Like Peptide 1 metabolism
Insulin metabolism
Insulin-Secreting Cells metabolism
Membrane Proteins metabolism
Receptors, Glucagon metabolism
Receptors, Progesterone metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1535-9484
- Volume :
- 13
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Molecular & cellular proteomics : MCP
- Publication Type :
- Academic Journal
- Accession number :
- 25044020
- Full Text :
- https://doi.org/10.1074/mcp.M114.040196