| First Author | Bruinsma S | Year | 2018 |
| Journal | J Biol Chem | Volume | 293 |
| Issue | 21 | Pages | 8217-8229 |
| PubMed ID | 29615494 | Mgi Jnum | J:264166 |
| Mgi Id | MGI:6192916 | Doi | 10.1074/jbc.RA117.001547 |
| Citation | Bruinsma S, et al. (2018) Small molecules that inhibit the late stage of Munc13-4-dependent secretory granule exocytosis in mast cells. J Biol Chem 293(21):8217-8229 |
| abstractText | Ca(2+)-dependent secretory granule fusion with the plasma membrane is the final step for the exocytic release of inflammatory mediators, neuropeptides, and peptide hormones. Secretory cells use a similar protein machinery at late steps in the regulated secretory pathway, employing protein isoforms from the Rab, Sec1/Munc18, Munc13/CAPS, SNARE, and synaptotagmin protein families. However, no small-molecule inhibitors of secretory granule exocytosis that target these proteins are currently available but could have clinical utility. Here we utilized a high-throughput screen of a 25,000-compound library that identified 129 small-molecule inhibitors of Ca(2+)-triggered secretory granule exocytosis in RBL-2H3 mast cells. These inhibitors broadly fell into six different chemical classes, and follow-up permeable cell and liposome fusion assays identified the target for one class of these inhibitors. A family of 2-aminobenzothiazoles (termed benzothiazole exocytosis inhibitors or bexins) was found to inhibit mast cell secretory granule fusion by acting on a Ca(2+)-dependent, C2 domain-containing priming factor, Munc13-4. Our findings further indicated that bexins interfere with Munc13-4-membrane interactions and thereby inhibit Munc13-4-dependent membrane fusion. We conclude that bexins represent a class of specific secretory pathway inhibitors with potential as therapeutic agents. |
