title: SUMO1 enhances cAMP-dependent exocytosis and glucagon secretion from pancreatic α-cells.
abstract: Post-translational modification by the small ubiquitin-like modifier-1 (SUMO1) limits insulin secretion from β-cells by inhibiting insulin exocytosis and glucagon-like peptide-1 (GLP-1) receptor signalling. The secretion of glucagon from α-cells is regulated in a manner opposite to that of insulin; it is inhibited by elevated glucose and GLP-1, and increased by adrenergic signalling. We therefore sought to determine whether SUMO1 modulates mouse and human α-cell function. Action potentials (APs), ion channel function and exocytosis in single α-cells from mice and humans, identified by glucagon immunostaining, and glucagon secretion from intact islets were measured. The effects of SUMO1 on α-cell function and the respective inhibitory and stimulatory effects of exendin 4 and adrenaline were examined. Upregulation of SUMO1 increased α-cell AP duration, frequency and amplitude, in part as a result of increased Ca(2+) channel activity that led to elevated exocytosis. The ability of SUMO1 to enhance α-cell exocytosis was cAMP-dependent and resulted from an increased L-type Ca(2+) current and a shift away from exocytosis dependent on non-L-type channels, an effect that was mimicked by knockdown of the deSUMOylating enzyme sentrin/SUMO-specific protease-1 (SENP1). Finally, although SUMO1 prevented GLP-1 receptor-mediated inhibition of α-cell Na(+) channels and single-cell exocytosis, it failed to prevent the exendin 4-mediated inhibition of glucagon secretion. Consistent with its cAMP dependence, however, SUMO1 enhanced α-cell exocytosis and glucagon secretion stimulated by adrenaline. Thus, by contrast with its inhibitory role in β-cell exocytosis, SUMO1 is a positive regulator of α-cell exocytosis and glucagon secretion under conditions of elevated cAMP.
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Dai
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Aliya F
authors.initials: AF
authors.lastname: Spigelman
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Shara
authors.initials: S
authors.lastname: Khan
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Matthias
authors.initials: M
authors.lastname: Braun
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada.
authors.forename: Jocelyn E
authors.initials: JE
authors.lastname: Manning Fox
authors.affiliation: Department of Pharmacology, University of Alberta, Edmonton, AB, Canada Alberta Diabetes Institute, University of Alberta, Edmonton, AB, Canada pmacdonald@ualberta.ca.
authors.forename: Patrick E
authors.initials: PE
authors.lastname: MacDonald
mesh_terms: D000200:Action Potentials; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005089:Exocytosis; D005934:Glucagon / Q000378:metabolism*; D000067757:Glucagon-Like Peptide-1 Receptor; D050416:Glucagon-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018027:Receptors, Glucagon / Q000819:agonists / Q000037:antagonists & inhibitors; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D018027:Receptors, Glucagon; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D005934:Glucagon; D012964:Sodium; D000242:Cyclic AMP; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases