Emerging roles for β-arrestin-1 in the control of the pancreatic β-cell function and mass: new therapeutic strategies and consequences for drug screening.
Defective insulin secretion is a feature of type 2 diabetes that results from inadequate compensatory increase in β-cell mass, decreased β-cell survival and impaired glucose-dependent insulin release. Pancreatic β-cell proliferation, survival and secretion are thought to be regulated by signalling pathways linked to G-protein coupled receptors (GPCRs), such as the glucagon-like peptide-1 (GLP-1) and the pituitary adenylate cyclase-activating polypeptide (PACAP) receptors. β-arrestin-1 serves as a multifunctional adaptor protein that mediates receptor desensitization, receptor internalization, and links GPCRs to downstream pathways such as tyrosine kinase Src, ERK1/2 or Akt/PKB. Importantly, recent studies found that β-arrestin-1 mediates GLP-1 signalling to insulin secretion, GLP-1 antiapoptotic effect by phosphorylating the proapoptotic protein Bad through ERK1/2 activation, and PACAP potentiation of glucose-induced long-lasting ERK1/2 activation controlling IRS-2 expression. Together, these novel findings reveal an important functional role for β-arrestin-1 in the regulation of insulin secretion and β-cell survival by GPCRs.
Dalle
Stéphane
S
INSERM U661, CNRS UMR 5203, Institut de Génomique Fonctionnelle, Université Montpellier I and II, Montpellier, France. stephane.dalle@igf.cnrs.fr
Ravier
Magalie A
MA
Bertrand
Gyslaine
G
D000818:Animals; D019390:Arrestins / Q000502:physiology*; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D004353:Drug Evaluation, Preclinical; D000067757:Glucagon-Like Peptide-1 Receptor; D005947:Glucose / Q000502:physiology; D006801:Humans; D050417:Insulin-Secreting Cells / Q000473:pathology / Q000502:physiology*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D018027:Receptors, Glucagon / Q000378:metabolism; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism; D015398:Signal Transduction; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D019390:Arrestins; C000593833:GLP1R protein, human; D000067757:Glucagon-Like Peptide-1 Receptor; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D051236:Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; D020794:Receptor Protein-Tyrosine Kinases; D005947:Glucose