Diabetes (New York, N.Y.), 2020-12, Vol.69 (12), p.2655-2666
2020
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Details
- Autor(en) / Beteiligte
- Titel
- Melanophilin Accelerates Insulin Granule Fusion without Predocking to the Plasma Membrane
- Ist Teil von
- Diabetes (New York, N.Y.), 2020-12, Vol.69 (12), p.2655-2666
- Ort / Verlag
- United States: American Diabetes Association
- Erscheinungsjahr
- 2020
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- Direct observation of fluorescence-labeled secretory granule exocytosis in living pancreatic β-cells has revealed heterogeneous prefusion behaviors: some granules dwell beneath the plasma membrane before fusion, while others fuse immediately once they are recruited to the plasma membrane. Although the former mode seems to follow sequential docking-priming-fusion steps as found in synaptic vesicle exocytosis, the latter mode, which is unique to secretory granule exocytosis, has not been explored well. Here, we show that melanophilin, one of the effectors of the monomeric guanosine-5'-triphosphatase Rab27 on the granule membrane, is involved in such an accelerated mode of exocytosis. Melanophilin-mutated mouse and melanophilin-downregulated human pancreatic β-cells both exhibit impaired glucose-stimulated insulin secretion, with a specific reduction in fusion events that bypass stable docking to the plasma membrane. Upon stimulus-induced [Ca ] rise, melanophilin mediates this type of fusion by dissociating granules from myosin-Va and actin in the actin cortex and by associating them with a fusion-competent, open form of syntaxin-4 on the plasma membrane. These findings provide the hitherto unknown mechanism to support sustainable exocytosis by which granules are recruited from the cell interior and fuse promptly without stable predocking to the plasma membrane.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0012-1797eISSN: 1939-327XDOI: 10.2337/db20-0069Titel-ID: cdi_proquest_miscellaneous_2447549047
- Format
- –
- Schlagworte
- Actin, Adaptor Proteins, Signal Transducing - genetics, Adaptor Proteins, Signal Transducing - metabolism, Animals, Beta cells, Calcium, Calcium (intracellular), Calcium - metabolism, Cell Membrane, Exocytosis, Gene Expression Regulation, Humans, Insulin, Insulin - metabolism, Insulin secretion, Membrane fusion, Mice, Myosin, Myosin Heavy Chains - genetics, Myosin Heavy Chains - metabolism, Myosin Type V - genetics, Myosin Type V - metabolism, Pancreas, Plasma, Qa-SNARE Proteins - genetics, Qa-SNARE Proteins - metabolism, rab27 GTP-Binding Proteins - genetics, rab27 GTP-Binding Proteins - metabolism, Syntaxin, Syntaxin 4, Triphosphatase