title: CXCL12 inhibits expression of the NMDA receptor's NR2B subunit through a histone deacetylase-dependent pathway contributing to neuronal survival.
abstract: Homeostatic chemokines, such as CXCL12, can affect neuronal activity by the regulation of inhibitory and excitatory neurotransmission, but the mechanisms involved are still undefined. Our previous studies have shown that CXCL12 protects cortical neurons from excitotoxicity by promoting the function of the gene-repressor protein Rb, which is involved in the recruitment of chromatin modifiers (such as histone deacetylases (HDACs)) to gene promoters. In neurons, Rb controls activity-dependent genes essential to neuronal plasticity and survival, such as the N-methyl-D-aspartic acid (NMDA) receptor's subunit NR2B, the expression of which in the tetrameric ion channel largely affects calcium signaling by glutamate. In this study, we report that CXCL12 differentially modulates intracellular responses after stimulation of synaptic and extrasynaptic NMDA receptors, by a specific regulation of the NR2B gene that involves HDACs. Our results show that CXCL12 selectively inhibits NR2B expression in vitro and in vivo altering NMDA-induced calcium responses associated with neuronal death, while promoting prosurvival pathways that depend on stimulation of synaptic receptors. Along with previous studies, these findings underline the role of CXCL12/CXCR4 in the regulation of crucial components of glutamatergic transmission. These novel effects of CXCL12 may be involved in the physiological function of the chemokine in both developing and mature brains.
authors.affiliation: Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA 19102, USA.
authors.forename: J
authors.initials: J
authors.lastname: Nicolai
authors.forename: S
authors.initials: S
authors.lastname: Burbassi
authors.forename: J
authors.initials: J
authors.lastname: Rubin
authors.forename: O
authors.initials: O
authors.lastname: Meucci
mesh_terms: D000818:Animals; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D019610:Cytoprotection / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D009498:Neurotoxins / Q000633:toxicity; D021122:Protein Subunits / Q000378:metabolism*; D051381:Rats; D019718:Receptors, CXCR4 / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D017981:Receptors, Neurotransmitter / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D056572:Histone Deacetylase Inhibitors; C121001:NR2B NMDA receptor; D009498:Neurotoxins; D021122:Protein Subunits; D019718:Receptors, CXCR4; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D016202:N-Methylaspartate; D006655:Histone Deacetylases