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- Title
SUMO1 enhances cAMP-dependent exocytosis and glucagon secretion from pancreatic α-cells.
- Authors
Dai, Xiao‐Qing; Spigelman, Aliya F.; Khan, Shara; Braun, Matthias; Manning Fox, Jocelyn E.; MacDonald, Patrick E.
- Abstract
Key points SUMOylation is the reversible modification of proteins by the attachment of small ubiquitin-like modifier (SUMO) peptides, which in pancreatic β-cells inhibits insulin exocytosis and glucagon-like peptide-1 (GLP-1) receptor signalling., We find in glucagon-secreting pancreatic α-cells that SUMOylation increases excitability and enhances exocytosis by increasing L-type Ca2+ currents., The ability of SUMOylation to facilitate α-cell exocytosis is cAMP-dependent, leading to enhanced adrenaline-stimulated glucagon secretion., SUMO1 prevents inhibition of α-cell Na+ current and exocytosis by a GLP-1 receptor agonist, but does not prevent GLP-1 receptor-dependent inhibition of glucagon secretion., SUMOylation modifies α-cell responses to cAMP-dependent signalling and, by contrast with its inhibitory effects in β-cells, enhances α-cell exocytosis and glucagon secretion., 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 Ca2+ 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 Ca2+ 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.
- Subjects
SMALL ubiquitin-related modifier proteins; EXOCYTOSIS; GLUCAGON-like peptide 1; INSULIN; SIGNAL peptides
- Publication
Journal of Physiology, 2014, Vol 592, Issue 17, p3715
- ISSN
0022-3751
- Publication type
Article
- DOI
10.1113/jphysiol.2014.274084