SUMO1 enhances cAMP‐dependent exocytosis and glucagon secretion from pancreatic α‐cells

Key points SUMOylation is the reversible modification of proteins by the attachment of s mall u biquitin‐like mo difier (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 Ca 2+ 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 s mall u biquitin‐like mo difier‐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.