Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse.
Details
Download: 36217825_BIB_CB0C41E63EA7.pdf (20919.58 [Ko])
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
State: Public
Version: Final published version
License: CC BY-NC-ND 4.0
Serval ID
serval:BIB_CB0C41E63EA7
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse.
Journal
The EMBO journal
ISSN
1460-2075 (Electronic)
ISSN-L
0261-4189
Publication state
Published
Issued date
17/11/2022
Peer-reviewed
Oui
Volume
41
Number
22
Pages
e110963
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Publication Status: ppublish
Abstract
Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, by combining mouse models of neuron-specific ATG5 deficiency in either excitatory or inhibitory neurons with quantitative proteomics, high-content microscopy, and live-imaging approaches, we show that autophagy protein ATG5 functions in neurons to regulate cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA-R1, which sequesters the PKA catalytic subunit and diminishes cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins that mediate AMPAR trafficking. Furthermore, ATG5 deletion in glutamatergic neurons augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.
Keywords
Mice, Animals, Synapses/metabolism, Neurons/metabolism, Cyclic AMP-Dependent Protein Kinases/metabolism, Signal Transduction, Autophagy, PKA, autophagy, brain, phosphorylation, synapse
Pubmed
Web of science
Create date
17/10/2022 14:29
Last modification date
25/01/2024 8:44