Controlling synaptotagmin activity by electrostatic screening

Nat Struct Mol Biol. 2012 Oct;19(10):991-7. doi: 10.1038/nsmb.2375. Epub 2012 Sep 2.

Abstract

Exocytosis of neurosecretory vesicles is mediated by the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins syntaxin-1, synaptobrevin and SNAP-25, with synaptotagmin functioning as the major Ca(2+) sensor for triggering membrane fusion. Here we show that bovine chromaffin granules readily fuse with large unilamellar liposomes in a SNARE-dependent manner. Fusion is enhanced by Ca(2+), but only when the target liposomes contain phosphatidylinositol-4,5-bisphosphate and when polyphosphate anions, such as nucleotides or pyrophosphate, are present. Ca(2+)-dependent enhancement is mediated by endogenous synaptotagmin-1. Polyphosphates operate by an electrostatic mechanism that reverses an inactivating cis association of synaptotagmin-1 with its own membrane without affecting trans binding. Hence, the balancing of trans- and cis-membrane interactions of synaptotagmin-1 could be a crucial element in the pathway of Ca(2+)-dependent exocytosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Calcium / metabolism
  • Cattle
  • Chromaffin Granules / chemistry
  • Chromaffin Granules / drug effects
  • Chromaffin Granules / metabolism*
  • Exocytosis / physiology
  • Liposomes / chemistry
  • Liposomes / metabolism
  • Membrane Fusion
  • Phosphatidylinositol 4,5-Diphosphate / metabolism
  • Phospholipids / chemistry
  • Phospholipids / metabolism
  • Polyphosphates / chemistry
  • Polyphosphates / metabolism
  • Rats
  • SNARE Proteins / metabolism
  • Static Electricity
  • Synaptosomal-Associated Protein 25 / metabolism
  • Synaptotagmin I / metabolism*
  • Syntaxin 1 / metabolism

Substances

  • Liposomes
  • Phosphatidylinositol 4,5-Diphosphate
  • Phospholipids
  • Polyphosphates
  • SNARE Proteins
  • Snap25 protein, rat
  • Synaptosomal-Associated Protein 25
  • Synaptotagmin I
  • Syntaxin 1
  • Adenosine Triphosphate
  • Calcium