Munc18-1 and Munc18-2 proteins modulate β-cell Ca 2+ sensitivity and kinetics of insulin exocytosis differently

Slavena A. Mandic, Masa Skelin, Jenny U. Johansson, Marjan S. Rupnik, Per Olof Berggren, Christina Bark

Research output: Contribution to journalArticle

21 Scopus citations

Abstract

Fast neurotransmission and slower hormone release share the same core fusion machinery consisting of SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. In evoked neurotransmission, interactions between SNAREs and the Munc18-1 protein, a member of the Sec1/Munc18 (SM) protein family, are essential for exocytosis, whereas other SM proteins are dispensable. To address if the exclusivity of Munc18-1 demonstrated in neuroexocytosis also applied to fast insulin secretion, we characterized the presence and function of Munc18-1 and its closest homologue Munc18-2 in β-cell stimulus-secretion coupling. We show that pancreatic β-cells express both Munc18-1 and Munc18-2. The two Munc18 homologues exhibit different subcellular localization, and only Munc18-1 redistributes in response to glucose stimulation. However, both Munc18-1 and Munc18-2 augment glucose-stimulated hormone release. Ramp-like photorelease of caged Ca 2+ and high resolution whole-cell patch clamp recordings show that Munc18-1 and Munc18-2 overexpression shift the Ca 2+ sensitivity of the fastest phase of insulin exocytosis differently. In addition, we reveal that Ca 2+ sensitivity of exocytosis in β-cells depends on the phosphorylation status of the Munc18 proteins. Even though Munc18-1 emerges as the key SM-protein determining the Ca 2+ threshold for triggering secretory activity in a stimulated β-cell, Munc18-2 has the ability to increase Ca 2+ sensitivity and thus mediates the release of fusion-competent granules requiring a lower cytoplasmic-free Ca 2+ concentration, [Ca 2+]i. Hence, Munc18-1 and Munc18-2 display distinct subcellular compartmentalization and can coordinate the insulin exocytotic process differently as a consequence of the actual [Ca 2+]i.

Original languageEnglish (US)
Pages (from-to)28026-28040
Number of pages15
JournalJournal of Biological Chemistry
Volume286
Issue number32
DOIs
StatePublished - Aug 12 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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    Mandic, S. A., Skelin, M., Johansson, J. U., Rupnik, M. S., Berggren, P. O., & Bark, C. (2011). Munc18-1 and Munc18-2 proteins modulate β-cell Ca 2+ sensitivity and kinetics of insulin exocytosis differently. Journal of Biological Chemistry, 286(32), 28026-28040. https://doi.org/10.1074/jbc.M111.235366