The RAB3-RIM Pathway Is Essential for the Release of Neuromodulators.
BDNF
MUNC13
NPY
RAB3
RIM1/2
SEC4
dense-core vesicles
neuromodulators
neuropeptide
secretion
Journal
Neuron
ISSN: 1097-4199
Titre abrégé: Neuron
Pays: United States
ID NLM: 8809320
Informations de publication
Date de publication:
18 12 2019
18 12 2019
Historique:
received:
15
03
2019
revised:
01
08
2019
accepted:
10
09
2019
pubmed:
5
11
2019
medline:
24
3
2020
entrez:
5
11
2019
Statut:
ppublish
Résumé
Secretion principles are conserved from yeast to humans, and many yeast orthologs have established roles in synaptic vesicle exocytosis in the mammalian brain. Surprisingly, SEC4 orthologs and their effectors, the exocyst, are dispensable for synaptic vesicle exocytosis. Here, we identify the SEC4 ortholog RAB3 and its neuronal effector, RIM1, as essential molecules for neuropeptide and neurotrophin release from dense-core vesicles (DCVs) in mammalian neurons. Inactivation of all four RAB3 genes nearly ablated DCV exocytosis, and re-expression of RAB3A restored this deficit. In RIM1/2-deficient neurons, DCV exocytosis was undetectable. Full-length RIM1, but not mutants that lack RAB3 or MUNC13 binding, restored release. Strikingly, a short N-terminal RIM1 fragment only harboring RAB3- and MUNC13-interacting domains was sufficient to support DCV exocytosis. We propose that RIM and MUNC13 emerged as mammalian alternatives to the yeast exocyst complex as essential RAB3/SEC4 effectors and organizers of DCV fusion sites by recruiting DCVs via RAB3.
Identifiants
pubmed: 31679900
pii: S0896-6273(19)30788-3
doi: 10.1016/j.neuron.2019.09.015
pmc: PMC6923582
mid: NIHMS1059003
pii:
doi:
Substances chimiques
Neurotransmitter Agents
0
GTP-Binding Proteins
EC 3.6.1.-
rab3 GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1065-1080.e12Subventions
Organisme : NIMH NIH HHS
ID : R01 MH113349
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS083898
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS103484
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
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