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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

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 – synaptotagm...

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Autores principales: Walter, Alexander M., Pinheiro, Paulo S., Verhage, Matthijs, Sørensen, Jakob B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854459/
https://www.ncbi.nlm.nih.gov/pubmed/24339761
http://dx.doi.org/10.1371/journal.pcbi.1003362
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author Walter, Alexander M.
Pinheiro, Paulo S.
Verhage, Matthijs
Sørensen, Jakob B.
author_facet Walter, Alexander M.
Pinheiro, Paulo S.
Verhage, Matthijs
Sørensen, Jakob B.
author_sort Walter, Alexander M.
collection PubMed
description 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.
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spelling pubmed-38544592013-12-11 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 Walter, Alexander M. Pinheiro, Paulo S. Verhage, Matthijs Sørensen, Jakob B. PLoS Comput Biol Research Article 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. Public Library of Science 2013-12-05 /pmc/articles/PMC3854459/ /pubmed/24339761 http://dx.doi.org/10.1371/journal.pcbi.1003362 Text en © 2013 Walter et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Walter, Alexander M.
Pinheiro, Paulo S.
Verhage, Matthijs
Sørensen, Jakob B.
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort sequential vesicle pool model with a single release sensor and a ca(2+)-dependent priming catalyst effectively explains ca(2+)-dependent properties of neurosecretion
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3854459/
https://www.ncbi.nlm.nih.gov/pubmed/24339761
http://dx.doi.org/10.1371/journal.pcbi.1003362
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