PMID- 37910253
OWN - NLM
STAT- MEDLINE
DCOM- 20231216
LR  - 20240301
IS  - 1939-4586 (Electronic)
IS  - 1059-1524 (Print)
IS  - 1059-1524 (Linking)
VI  - 35
IP  - 1
DP  - 2024 Jan 1
TI  - Neuronal membrane proteasome-derived peptides modulate NMDAR-dependent neuronal 
      signaling to promote changes in gene expression.
PG  - ar6
LID - 10.1091/mbc.E23-06-0218 [doi]
LID - ar6
AB  - The neuronal membrane proteasome (NMP) degrades intracellular proteins into 
      peptides that are released directly into the extracellular space, whereby they 
      stimulate neurons to promote signaling mechanisms that remain unknown. Here, we 
      demonstrate that neuronal stimulation promotes NMP activity and, subsequently, 
      enhanced production of NMP peptides. We show that these neuronal 
      activity-dependent NMP peptides can rapidly promote N-methyl-D-aspartate receptor 
      (NMDAR)-dependent calcium influx in neurons. This leads to sustained 
      phosphorylation of the well-defined stimulus-induced transcription factor, cyclic 
      AMP response element (CRE)-binding protein (CREB). Downstream of these events, we 
      identified changes to neuronal target genes which included increased expression 
      of immediate early genes (e.g., Fos, Npas4, Egr4) and other genes known to have 
      critical neuroregulatory roles. Further observations led to the discovery that 
      NMP peptide-induced changes in gene expression is dependent on NMDARs and 
      independent of AMPA receptors or voltage-gated sodium channels. These data 
      demonstrate that NMP peptides are endogenous and selective activators of NMDA 
      receptors and act as sufficient and novel stimuli within the context of neuronal 
      activity-dependent signaling. This novel pathway is parallel to classic neuronal 
      activity-dependent programs and points to NMP and its resulting peptides as 
      potential modulators of neuronal function.
FAU - Turker, Fulya
AU  - Turker F
AD  - Department of Biological Chemistry, The Johns Hopkins University, School of 
      Medicine, Baltimore, MD 21205.
FAU - Brennan, Anna
AU  - Brennan A
AD  - Department of Biological Chemistry, The Johns Hopkins University, School of 
      Medicine, Baltimore, MD 21205.
FAU - Margolis, Seth S
AU  - Margolis SS
AD  - Department of Biological Chemistry, The Johns Hopkins University, School of 
      Medicine, Baltimore, MD 21205.
AD  - Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School 
      of Medicine, Baltimore, MD 21205.
LA  - eng
GR  - R01 NS110754/NS/NINDS NIH HHS/United States
PT  - Journal Article
DEP - 20231101
PL  - United States
TA  - Mol Biol Cell
JT  - Molecular biology of the cell
JID - 9201390
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - EC 3.4.25.1 (Proteasome Endopeptidase Complex)
RN  - 0 (Peptides)
RN  - 0 (Cyclic AMP Response Element-Binding Protein)
RN  - SY7Q814VUP (Calcium)
SB  - IM
MH  - *Receptors, N-Methyl-D-Aspartate/genetics/metabolism
MH  - *Proteasome Endopeptidase Complex/metabolism
MH  - Neurons/metabolism
MH  - Peptides/metabolism
MH  - Cyclic AMP Response Element-Binding Protein/genetics/metabolism
MH  - Gene Expression
MH  - Calcium/metabolism
PMC - PMC10881162
EDAT- 2023/11/01 18:44
MHDA- 2023/12/17 13:19
PMCR- 2024/02/29
CRDT- 2023/11/01 12:06
PHST- 2023/12/17 13:19 [medline]
PHST- 2023/11/01 18:44 [pubmed]
PHST- 2023/11/01 12:06 [entrez]
PHST- 2024/02/29 00:00 [pmc-release]
AID - E23-06-0218 [pii]
AID - 10.1091/mbc.E23-06-0218 [doi]
PST - ppublish
SO  - Mol Biol Cell. 2024 Jan 1;35(1):ar6. doi: 10.1091/mbc.E23-06-0218. Epub 2023 Nov 
      1.