Recent New Insights Into the Role of SNARE and Associated Proteins in Insulin Granule Exocytosis

Diabetes Obes Metab. 2017 Sep;19 Suppl 1:115-123. doi: 10.1111/dom.13001.

Abstract

Initial work on the exocytotic machinery of predocked insulin secretory granules (SGs) in pancreatic β-cells mimicked the SNARE hypothesis work in neurons, which includes SM/SNARE complex and associated priming proteins, fusion clamps and Ca2+ sensors. However, β-cell SGs, unlike neuronal synaptic vesicles, exhibit a biphasic secretory response that requires additional distinct features in exocytosis including newcomer SGs that undergo minimal docking time at the plasma membrane (PM) before fusion and multi-SG (compound) fusion. These exocytotic events are mediated by Munc18/SNARE complexes distinct from that which mediates predocked SG fusion. We review some recent insights in SNARE complex assembly and the promiscuity in SM/SNARE complex formation, whereby both contribute to conferring different insulin SG fusion kinetics. Some SNARE and associated proteins play non-fusion roles, including tethering SGs to Ca2+ channels, SG recruitment from cell interior to PM, and inhibitory SNAREs that block the action of profusion SNAREs. We discuss new insights into how sub-PM cytoskeletal mesh gates SG access to the PM and the targeting of SG exocytosis to PM domains in functionally polarized β-cells within intact islets. These recent developments have major implications on devising clever SNARE replacement therapies that could restore the deficient insulin secretion in diabetic islet β-cells.

Keywords: SNARE proteins; insulin secretion; newcomer granules.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium Signaling
  • Cell Membrane / metabolism
  • Exocytosis*
  • Humans
  • Insulin / metabolism*
  • Insulin Secretion
  • Insulin-Secreting Cells / metabolism*
  • Kinetics
  • Membrane Fusion
  • Munc18 Proteins / chemistry
  • Munc18 Proteins / metabolism*
  • Protein Multimerization
  • SNARE Proteins / chemistry
  • SNARE Proteins / metabolism*
  • Secretory Pathway
  • Secretory Vesicles / metabolism*

Substances

  • Insulin
  • Munc18 Proteins
  • SNARE Proteins