SUMO1 enhances cAMP‐dependent exocytosis and glucagon secretion from pancreatic α‐cells
Bibliographic record
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.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".