A sequential vesicle pool model with a single release sensor and a Ca(2+)-dependent priming catalyst effectively explains Ca(2+)-dependent properties of neurosecretion

PLoS Comput Biol. 2013;9(12):e1003362. doi: 10.1371/journal.pcbi.1003362. Epub 2013 Dec 5.

Abstract

Neurotransmitter release depends on the fusion of secretory vesicles with the plasma membrane and the release of their contents. The final fusion step displays higher-order Ca(2+) dependence, but also upstream steps depend on Ca(2+). After deletion of the Ca(2+) sensor for fast release - synaptotagmin-1 - slower Ca(2+)-dependent release components persist. These findings have provoked working models involving parallel releasable vesicle pools (Parallel Pool Models, PPM) driven by alternative Ca(2+) sensors for release, but no slow release sensor acting on a parallel vesicle pool has been identified. We here propose a Sequential Pool Model (SPM), assuming a novel Ca(2+)-dependent action: a Ca(2+)-dependent catalyst that accelerates both forward and reverse priming reactions. While both models account for fast fusion from the Readily-Releasable Pool (RRP) under control of synaptotagmin-1, the origins of slow release differ. In the SPM the slow release component is attributed to the Ca(2+)-dependent refilling of the RRP from a Non-Releasable upstream Pool (NRP), whereas the PPM attributes slow release to a separate slowly-releasable vesicle pool. Using numerical integration we compared model predictions to data from mouse chromaffin cells. Like the PPM, the SPM explains biphasic release, Ca(2+)-dependence and pool sizes in mouse chromaffin cells. In addition, the SPM accounts for the rapid recovery of the fast component after strong stimulation, where the PPM fails. The SPM also predicts the simultaneous changes in release rate and amplitude seen when mutating the SNARE-complex. Finally, it can account for the loss of fast- and the persistence of slow release in the synaptotagmin-1 knockout by assuming that the RRP is depleted, leading to slow and Ca(2+)-dependent fusion from the NRP. We conclude that the elusive 'alternative Ca(2+) sensor' for slow release might be the upstream priming catalyst, and that a sequential model effectively explains Ca(2+)-dependent properties of secretion without assuming parallel pools or sensors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium / metabolism*
  • Chromaffin Cells / metabolism
  • Kinetics
  • Mice
  • Models, Biological*
  • Neurosecretion*
  • SNARE Proteins / metabolism

Substances

  • SNARE Proteins
  • Calcium

Grants and funding

This work was supported by EMBO (Longterm Fellowship to AMW), the European Union Seventh Framework Programme under grant agreement no. HEALTH-F2-2009-242167 (“SynSys” project to MV and JBS), and the Lundbeck Foundation (Junior Group Leader Fellowship, JBS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.