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J Biol Chem. 2018 May 25;293(21):8217-8229. doi: 10.1074/jbc.RA117.001547. Epub 2018 Apr 3.

Small molecules that inhibit the late stage of Munc13-4-dependent secretory granule exocytosis in mast cells.

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From the Department of Biochemistry, University of Wisconsin, Madison Wisconsin 53706.
From the Department of Biochemistry, University of Wisconsin, Madison Wisconsin 53706


Ca2+-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 Ca2+-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 Ca2+-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.


Munc13-4; exocytosis; inhibitor; intracellular trafficking; mast cell; membrane fusion; secretion; small molecule

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