Identification of a Munc13-sensitive step in chromaffin cell large dense-core vesicle exocytosis

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Abstract

It is currently unknown whether the molecular steps of large dense-core vesicle (LDCV) docking and priming are identical to the corresponding reactions in synaptic vesicle (SV) exocytosis. Munc13s are essential for SV docking and priming, and we systematically analyzed their role in LDCV exocytosis using chromaffin cells lacking individual isoforms. We show that particularly Munc13-2 plays a fundamental role in LDCV exocytosis, but in contrast to synapses lacking Munc13s, the corresponding chromaffin cells do not exhibit a vesicle docking defect. We further demonstrate that ubMunc13-2 and Munc13-1 confer Ca²⁺-dependent LDCV priming with similar affinities, but distinct kinetics. Using a mathematical model, we identify an early LDCV priming step that is strongly dependent upon Munc13s. Our data demonstrate that the molecular steps of SV and LDCV priming are very similar while SV and LDCV docking mechanisms are distinct.

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Kwun-nok Mimi Man

Department of Molecular Neurobiology, Max-Planck-Institut fuer Experimentelle Medizin, Göttingen, Germany

Competing interests
The authors declare that no competing interests exist.
Cordelia Imig

Department of Molecular Neurobiology, Max-Planck-Institut fuer Experimentelle Medizin, Göttingen, Germany

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The authors declare that no competing interests exist.
Alexander Matthias Walter

Leibniz-Institute for Molecular Pharmacology, Berlin, Germany

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The authors declare that no competing interests exist.
Paulo S Pinheiro

Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Lundbeck Foundation Center for Biomembranes in Nanomedicine, University of Copenhagen, Copenhagen, Denmark

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The authors declare that no competing interests exist.
David R Stevens

Department of Physiology, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Jens Rettig

Department of Physiology, Saarland University, Homburg, Germany

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The authors declare that no competing interests exist.
Jakob B Sørensen

Department of Neuroscience and Pharmacology, Faculty of Health and Medical Sciences, Lundbeck Foundation Center for Biomembranes in Nanomedicine, University of Copenhagen, Copenhagen, Denmark

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The authors declare that no competing interests exist.
Benjamin H Cooper

Department of Molecular Neurobiology, Max-Planck-Institut fuer Experimentelle Medizin, Göttingen, Germany

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The authors declare that no competing interests exist.
Nils Brose

Department of Molecular Neurobiology, Max-Planck-Institut fuer Experimentelle Medizin, Göttingen, Germany

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The authors declare that no competing interests exist.
Sonja M Wojcik

Department of Molecular Neurobiology, Max-Planck-Institut fuer Experimentelle Medizin, Göttingen, Germany

For correspondence
wojcik@em.mpg.de

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: All experiments were performed in compliance with the regulations of the local Animal Care and Use Committee of Lower Saxony, Oldenburg, Germany.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.