Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles

Enqi He, Keimpe Wierda, Rhode Van Westen, Jurjen H. Broeke, Ruud F. Toonen, L. Niels Cornelisse, Matthijs Verhage

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of N-ethylmaleimide sensitive factor (NSF), N-ethylmaleimide (NEM) or interfering peptides, prevent de-priming in munc18-1/2SWAP or munc13-1 null synapses, but not in CAPS-1/2 null, another priming-deficient mutant. NEM rescues synaptic transmission in munc13-1 null and munc18-1/2SWAP synapses, in acute munc13-1 null slices and even partially in munc13-1/2 double null synapses. Together these data indicate that Munc13-1 and Munc18-1, but not CAPS-1/2, stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.

Original languageEnglish
Article number15915
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 21 Jun 2017

Cite this

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title = "Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles",
abstract = "Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of N-ethylmaleimide sensitive factor (NSF), N-ethylmaleimide (NEM) or interfering peptides, prevent de-priming in munc18-1/2SWAP or munc13-1 null synapses, but not in CAPS-1/2 null, another priming-deficient mutant. NEM rescues synaptic transmission in munc13-1 null and munc18-1/2SWAP synapses, in acute munc13-1 null slices and even partially in munc13-1/2 double null synapses. Together these data indicate that Munc13-1 and Munc18-1, but not CAPS-1/2, stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.",
author = "Enqi He and Keimpe Wierda and {Van Westen}, Rhode and Broeke, {Jurjen H.} and Toonen, {Ruud F.} and Cornelisse, {L. Niels} and Matthijs Verhage",
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doi = "10.1038/ncomms15915",
language = "English",
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Munc13-1 and Munc18-1 together prevent NSF-dependent de-priming of synaptic vesicles. / He, Enqi; Wierda, Keimpe; Van Westen, Rhode; Broeke, Jurjen H.; Toonen, Ruud F.; Cornelisse, L. Niels; Verhage, Matthijs.

In: Nature Communications, Vol. 8, 15915, 21.06.2017.

Research output: Contribution to journalArticleAcademicpeer-review

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AU - Broeke, Jurjen H.

AU - Toonen, Ruud F.

AU - Cornelisse, L. Niels

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AB - Synaptic transmission requires a stable pool of release-ready (primed) vesicles. Here we show that two molecules involved in SNARE-complex assembly, Munc13-1 and Munc18-1, together stabilize release-ready vesicles by preventing de-priming. Replacing neuronal Munc18-1 by a non-neuronal isoform Munc18-2 (Munc18-1/2SWAP) supports activity-dependent priming, but primed vesicles fall back into a non-releasable state (de-prime) within seconds. Munc13-1 deficiency produces a similar defect. Inhibitors of N-ethylmaleimide sensitive factor (NSF), N-ethylmaleimide (NEM) or interfering peptides, prevent de-priming in munc18-1/2SWAP or munc13-1 null synapses, but not in CAPS-1/2 null, another priming-deficient mutant. NEM rescues synaptic transmission in munc13-1 null and munc18-1/2SWAP synapses, in acute munc13-1 null slices and even partially in munc13-1/2 double null synapses. Together these data indicate that Munc13-1 and Munc18-1, but not CAPS-1/2, stabilize primed synaptic vesicles by preventing NSF-dependent de-priming.

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