| 摘要 |
Munc18 proteins facilitate formation of SNARE complexes known to mediate membrane fusion. Much is known about the fusion of secretory granule (SG) to plasma membrane, mediated by Munc18a-SNARE complexes. It has been found that another Munc18 isoform, Munc18b, mediates SG-SG fusion which causes potentiation of secretion. The present invention has identified specific site mutations within Munc18b which further increased (called KR mutant) or reduced (called E59K mutant) SG-SG fusion compared to wild type (WT) Munc18b, causing amplification or reduction of insulin secretion, respectively. Compounds identified that mimic the actions of Munc18b-WT and Munc18b-KR mutant which increase SG-SG fusion, and those which mimic Munc18b-E59K mutant that block SG-SG fusion, are useful for treating and/or preventing diseases and/or conditions, whose underlying bases are a deficiency or excess of SG-SG fusion, respectively. These compounds also include conserved domains in Munc18a and Munc18c that mimic the KR and E59K sites in Munc18b.
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