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[摘要]：Neurexins are a family of transmembrane, synaptic adhesion molecules. In neurons, neurexins bind to both sub-plasma membrane and synaptic vesicle-associated constituents of the secretory machinery, play a key role in the organization and stabilization of the presynaptic active zone, and help mediate docking of synaptic vesicles. We have previously shown that neurexins, like many other protein constituents of the neurotransmitter exocytotic machinery, are expressed in pancreatic beta cells. We hypothesized that the role of neurexins in beta cells parallels their role in neurons, with beta-cell neurexins helping to mediate insulin granule docking and secretion. Here we demonstrate that beta cells express a more restricted pattern of neurexin transcripts than neurons, with a clear predominance of neurexin-1 alpha expressed in isolated islets. Using INS-1E beta cells, we found that neurexin-1 alpha interacts with membrane-bound components of the secretory granule-docking machinery and with the granule-associated protein granuphilin. Decreased expression of neurexin-1 alpha, like decreased expression of granuphilin, reduces granule docking at the beta-cell membrane and improves insulin secretion. Perifusion of neurexin-1 alpha KO mouse islets revealed a significant increase in second-phase insulin secretion with a trend toward increased first-phase secretion. Upon glucose stimulation, neurexin-1 alpha protein levels decrease. This glucose-induced down-regulation may enhance glucose-stimulated insulin secretion. We conclude that neurexin-1 alpha is a component of the beta-cell secretory machinery and contributes to secretory granule docking, most likely through interactions with granuphilin. Neurexin-1 alpha is the only transmembrane component of the docking machinery identified thus far. Our findings provide new insights into the mechanisms of insulin granule docking and exocytosis. |
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