Endosomal phosphatidylinositol 3-phosphate controls synaptic vesicle cycling and neurotransmission.
endocytosis
endosomes
neurotransmission
phosphatidylinositol 3-phosphate
synaptic vesicle
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
02 05 2022
02 05 2022
Historique:
revised:
24
02
2022
received:
02
08
2021
accepted:
01
03
2022
pubmed:
24
3
2022
medline:
4
5
2022
entrez:
23
3
2022
Statut:
ppublish
Résumé
Neural circuit function requires mechanisms for controlling neurotransmitter release and the activity of neuronal networks, including modulation by synaptic contacts, synaptic plasticity, and homeostatic scaling. However, how neurons intrinsically monitor and feedback control presynaptic neurotransmitter release and synaptic vesicle (SV) recycling to restrict neuronal network activity remains poorly understood at the molecular level. Here, we investigated the reciprocal interplay between neuronal endosomes, organelles of central importance for the function of synapses, and synaptic activity. We show that elevated neuronal activity represses the synthesis of endosomal lipid phosphatidylinositol 3-phosphate [PI(3)P] by the lipid kinase VPS34. Neuronal activity in turn is regulated by endosomal PI(3)P, the depletion of which reduces neurotransmission as a consequence of perturbed SV endocytosis. We find that this mechanism involves Calpain 2-mediated hyperactivation of Cdk5 downstream of receptor- and activity-dependent calcium influx. Our results unravel an unexpected function for PI(3)P-containing neuronal endosomes in the control of presynaptic vesicle cycling and neurotransmission, which may explain the involvement of the PI(3)P-producing VPS34 kinase in neurological disease and neurodegeneration.
Identifiants
pubmed: 35318705
doi: 10.15252/embj.2021109352
pmc: PMC9058544
doi:
Substances chimiques
Neurotransmitter Agents
0
Phosphatidylinositol Phosphates
0
phosphatidylinositol 3-phosphate
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e109352Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
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