PMID- 32393578 OWN - NLM STAT- MEDLINE DCOM- 20210105 LR - 20221001 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 295 IP - 25 DP - 2020 Jun 19 TI - The NMDA receptor subunit GluN3A regulates synaptic activity-induced and myocyte enhancer factor 2C (MEF2C)-dependent transcription. PG - 8613-8627 LID - 10.1074/jbc.RA119.010266 [doi] AB - N-Methyl-d-aspartate type glutamate receptors (NMDARs) are key mediators of synaptic activity-regulated gene transcription in neurons, both during development and in the adult brain. Developmental differences in the glutamate receptor ionotropic NMDA 2 (GluN2) subunit composition of NMDARs determines whether they activate the transcription factor cAMP-responsive element-binding protein 1 (CREB). However, whether the developmentally regulated GluN3A subunit also modulates NMDAR-induced transcription is unknown. Here, using an array of techniques, including quantitative real-time PCR, immunostaining, reporter gene assays, RNA-Seq, and two-photon glutamate uncaging with calcium imaging, we show that knocking down GluN3A in rat hippocampal neurons promotes the inducible transcription of a subset of NMDAR-sensitive genes. We found that this enhancement is mediated by the accumulation of phosphorylated p38 mitogen-activated protein kinase in the nucleus, which drives the activation of the transcription factor myocyte enhancer factor 2C (MEF2C) and promotes the transcription of a subset of synaptic activity-induced genes, including brain-derived neurotrophic factor (Bdnf) and activity-regulated cytoskeleton-associated protein (Arc). Our evidence that GluN3A regulates MEF2C-dependent transcription reveals a novel mechanism by which NMDAR subunit composition confers specificity to the program of synaptic activity-regulated gene transcription in developing neurons. CI - (c) 2020 Chen et al. FAU - Chen, Liang-Fu AU - Chen LF AD - Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA. FAU - Lyons, Michelle R AU - Lyons MR AD - Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA. FAU - Liu, Fang AU - Liu F AD - Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA. FAU - Green, Matthew V AU - Green MV AD - Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA. FAU - Hedrick, Nathan G AU - Hedrick NG AD - Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA. FAU - Williams, Ashley B AU - Williams AB AD - Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA. FAU - Narayanan, Arthy AU - Narayanan A AD - Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA. FAU - Yasuda, Ryohei AU - Yasuda R AD - Max Planck Florida Institute for Neuroscience, Jupiter, Florida, USA. FAU - West, Anne E AU - West AE AUID- ORCID: 0000-0003-0846-139X AD - Department of Neurobiology, Duke University Medical Center, Durham, North Carolina, USA west@neuro.duke.edu. LA - eng GR - DP1 NS096787/NS/NINDS NIH HHS/United States GR - R01 MH080047/MH/NIMH NIH HHS/United States GR - R01 NS098804/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200511 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (Bdnf protein, rat) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (Cytoskeletal Proteins) RN - 0 (Grin3a protein, rat) RN - 0 (MEF2 Transcription Factors) RN - 0 (MEF2C protein, rat) RN - 0 (Membrane Glycoproteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (activity regulated cytoskeletal-associated protein) RN - 4368-28-9 (Tetrodotoxin) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - SY7Q814VUP (Calcium) SB - IM MH - Animals MH - Brain-Derived Neurotrophic Factor/genetics/metabolism MH - Calcium/metabolism MH - Cell Nucleus/metabolism MH - Cytoskeletal Proteins/genetics/metabolism MH - Female MH - Hippocampus/metabolism MH - MEF2 Transcription Factors/metabolism MH - Male MH - Membrane Glycoproteins/antagonists & inhibitors/genetics/*metabolism MH - Nerve Tissue Proteins/genetics/metabolism MH - Neuronal Plasticity/*physiology MH - Phosphorylation MH - RNA Interference MH - RNA, Small Interfering/metabolism MH - Rats MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Tetrodotoxin/pharmacology MH - *Transcription, Genetic/drug effects MH - p38 Mitogen-Activated Protein Kinases/metabolism PMC - PMC7307204 OTO - NOTNLM OT - MEF2 transcription factors OT - NMDAR) OT - N-methyl-d-aspartate receptor (NMDA receptor OT - brain-derived neurotrophic factor (BDNF) OT - excitation-transcription coupling OT - gene regulation OT - glutamate receptor ionotropic NMDA (GluN) OT - ionotropic glutamate receptor OT - mitogen-activated protein kinase (MAPK) signaling OT - neurodevelopment OT - p38 MAPK OT - synaptic activity COIS- Conflict of interest-The authors declare that they have no conflicts of interest with the contents of this article. EDAT- 2020/05/13 06:00 MHDA- 2021/01/06 06:00 PMCR- 2021/06/19 CRDT- 2020/05/13 06:00 PHST- 2019/07/19 00:00 [received] PHST- 2020/05/01 00:00 [revised] PHST- 2020/05/13 06:00 [pubmed] PHST- 2021/01/06 06:00 [medline] PHST- 2020/05/13 06:00 [entrez] PHST- 2021/06/19 00:00 [pmc-release] AID - S0021-9258(17)49254-4 [pii] AID - RA119.010266 [pii] AID - 10.1074/jbc.RA119.010266 [doi] PST - ppublish SO - J Biol Chem. 2020 Jun 19;295(25):8613-8627. doi: 10.1074/jbc.RA119.010266. Epub 2020 May 11.