Dataset Information


Munc18-1 regulates first-phase insulin release by promoting granule docking to multiple syntaxin isoforms.

ABSTRACT: Attenuated levels of the Sec1/Munc18 (SM) protein Munc18-1 in human islet ?-cells is coincident with type 2 diabetes, although how Munc18-1 facilitates insulin secretion remains enigmatic. Herein, using conventional Munc18-1(+/-) and ?-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 ?20% increase in pre-docked granule number. Pre-docked syntaxin 1-based SNARE complexes bound by Munc18-1 were detected in ?-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.


PROVIDER: S-EPMC3406668 | BioStudies | 2012-01-01T00:00:00Z

REPOSITORIES: biostudies

Similar Datasets

2007-01-01 | S-EPMC1815244 | BioStudies
2013-01-01 | S-EPMC3569727 | BioStudies
1000-01-01 | S-EPMC3761595 | BioStudies
2009-01-01 | S-EPMC2777098 | BioStudies
1000-01-01 | S-EPMC3438936 | BioStudies
2018-01-01 | S-EPMC6320071 | BioStudies
2010-01-01 | S-EPMC3012463 | BioStudies
2013-01-01 | S-EPMC3725074 | BioStudies
2010-01-01 | S-EPMC2834481 | BioStudies
2008-01-01 | S-EPMC2685195 | BioStudies