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 Ca2+ dependence, but also upstream steps depend on Ca2+. After deletion of the Ca2+ sensor for fast release – synaptotagmin-1 – slower Ca2+-dependent release components persist. These findings have provoked working models involving parallel releasable vesicle pools (Parallel Pool Models, PPM) driven by alternative Ca2+ 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 Ca2+-dependent action: a Ca2+-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 Ca2+-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, Ca2+-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 Ca2+-dependent fusion from the NRP. We conclude that the elusive ‘alternative Ca2+ sensor’ for slow release might be the upstream priming catalyst, and that a sequential model effectively explains Ca2+-dependent properties of secretion without assuming parallel pools or sensors.
Highlights
Neurotransmitter release and synaptic transmission depend on the fusion of secretory vesicles with the plasma membrane by exocytosis, and the ensuing release of the contained neurotransmitter molecules
Sequential and parallel vesicle pool models In order to explain the complex Ca2+-dependent properties of regulated exocytosis, we investigated a mathematical model with led to the suggestion of multiple sensors in parallel either controlling a single [19,20] or different vesicle pools [17]: in the absence of syt, a second release sensor would drive fusion
Despite the fact that parallel pathways have been the working model for more than a decade, molecular correlates of the slow release pathway are still missing: syt-1, syt-2 and syt-9 are widely accepted to be Ca2+ sensors for fast release [21], and detailed roles for many other proteins in fast release have been identified in vivo and reconstituted in vitro, including SNAREs, Munc13/CAPS and Munc18 [22], but no similar set of proteins dedicated to slow release is known
Summary
Neurotransmitter release and synaptic transmission depend on the fusion of secretory vesicles with the plasma membrane by exocytosis, and the ensuing release of the contained neurotransmitter molecules. Most working models assumed Ca2+-dependent vesicle priming and neurotransmitter release through a sequential pathway with one release sensor [11,12]. To account for the observation of kinetically distinct (i.e. fast and slow) release phases, models incorporated different releasable vesicle populations, or pools [13,14,15,16]. These pools deviated from each other either in terms of molecular composition or localization with respect to Ca2+ channels.
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