| First Author | Oh E | Year | 2012 |
| Journal | J Biol Chem | Volume | 287 |
| Issue | 31 | Pages | 25821-33 |
| PubMed ID | 22685295 | Mgi Jnum | J:188845 |
| Mgi Id | MGI:5442452 | Doi | 10.1074/jbc.M112.361501 |
| Citation | Oh E, et al. (2012) Munc18-1 regulates first-phase insulin release by promoting granule docking to multiple syntaxin isoforms. J Biol Chem 287(31):25821-33 |
| abstractText | Attenuated levels of the Sec1/Munc18 (SM) protein Munc18-1 in human islet beta-cells is coincident with type 2 diabetes, although how Munc18-1 facilitates insulin secretion remains enigmatic. Herein, using conventional Munc18-1(+/-) and beta-cell specific Munc18-1(-/-) knock-out mice, we establish that Munc18-1 is required for the first phase of insulin secretion. Conversely, human islets expressing elevated levels of Munc18-1 elicited significant potentiation of only first-phase insulin release. Insulin secretory changes positively correlated with insulin granule number at the plasma membrane: Munc18-1-deficient cells lacked 35% of the normal component of pre-docked insulin secretory granules, whereas cells with elevated levels of Munc18-1 exhibited a approximately 20% increase in pre-docked granule number. Pre-docked syntaxin 1-based SNARE complexes bound by Munc18-1 were detected in beta-cell lysates but, surprisingly, were reduced by elevation of Munc18-1 levels. Paradoxically, elevated Munc18-1 levels coincided with increased binding of syntaxin 4 to VAMP2 at the plasma membrane. Accordingly, syntaxin 4 was a requisite for Munc18-1 potentiation of insulin release. Munc18c, the cognate SM isoform for syntaxin 4, failed to bind SNARE complexes. Given that Munc18-1 does not pair with syntaxin 4, these data suggest a novel indirect role for Munc18-1 in facilitating syntaxin 4-mediated granule pre-docking to support first-phase insulin exocytosis. |
