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Regulated Membrane Fusion

We are focusing our studies on regulated membrane fusion, a molecular mechanism that is mediating both synaptic transmission and hormonal secretion. Regulated fusion of intracellular membrane vesicles with the plasma membrane is preceded by vesicular trafficking, formation of different vesicle pools and mobilization of fusion-competent vesicles. Ca2+-triggered fusion requires a SNARE complex composed of SNAP-25, VAMP and Syntaxin proteins. The SNARE complex has intrinsic capacity to mediate fusion but additional partner proteins are required to guarantee speed and accuracy of the release of signaling substances. Impairment of these processes can result in neuropsychiatric or metabolic disorders.

In order to better understand the molecular mechanisms leading to vesicular membrane fusion, we are combining in vitro systems where basic information can be extracted, with controlled in vivo systems, usually gene targeted mouse mutants, where the significance of a particular protein or a regulatory step can be analyzed in a physiologically relevant setting. We are also applying the technology and the preclinical research tools developed within our projects in a clinical setting by analyzing membrane fusion mechanisms in patients demonstrating deficiencies in hormonal secretion.

Research group: Growth and Metabolism - Diabetes and its complications

Selected publications

SNAP-25b-deficiency increases insulin secretion and changes spatiotemporal profile of Caoscillations in β cell networks.
Daraio T, Bombek L, Gosak M, Valladolid-Acebes I, Klemen M, Refai E, et al
Sci Rep 2017 Aug;7(1):7744

Replacing SNAP-25b with SNAP-25a expression results in metabolic disease.
Valladolid-Acebes I, Daraio T, Brismar K, Harkany T, Ögren S, Hökfelt T, et al
Proc. Natl. Acad. Sci. U.S.A. 2015 Aug;112(31):E4326-35

Munc18-1 and Munc18-2 proteins modulate beta-cell Ca2+ sensitivity and kinetics of insulin exocytosis differently.
Mandic S, Skelin M, Johansson J, Rupnik M, Berggren P, Bark C
J. Biol. Chem. 2011 Aug;286(32):28026-40

An ancient duplication of exon 5 in the Snap25 gene is required for complex neuronal development/function.
Johansson J, Ericsson J, Janson J, Beraki S, Stanić D, Mandic S, et al
PLoS Genet. 2008 Nov;4(11):e1000278

Neuronal calcium sensor-1 potentiates glucose-dependent exocytosis in pancreatic beta cells through activation of phosphatidylinositol 4-kinase beta.
Gromada J, Bark C, Smidt K, Efanov A, Janson J, Mandic S, et al
Proc. Natl. Acad. Sci. U.S.A. 2005 Jul;102(29):10303-8

Cyclin-dependent kinase 5 activators p35 and p39 facilitate formation of functional synapses.
Johansson J, Lilja L, Chen X, Higashida H, Meister B, Noda M, et al
Brain Res. Mol. Brain Res. 2005 Aug;138(2):215-27

Cyclin-dependent kinase 5 associated with p39 promotes Munc18-1 phosphorylation and Ca(2+)-dependent exocytosis.
Lilja L, Johansson J, Gromada J, Mandic S, Fried G, Berggren P, et al
J. Biol. Chem. 2004 Jul;279(28):29534-41


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