title: CXCR4 and NMDA Receptors Are Functionally Coupled in Rat Hippocampal Noradrenergic and Glutamatergic Nerve Endings.
abstract: Previous studies had shown that the HIV-1 capsidic glycoprotein gp120 (strain IIIB) modulates presynaptic release-regulating NMDA receptors on noradrenergic and glutamatergic terminals. This study aims to assess whether the chemokine CXC4 receptors (CXCR4s) has a role in the gp120-mediated effects. The effect of CXCL12, the endogenous ligand at CXCR4, on the NMDA-mediated releasing activity was therefore investigated. Rat hippocampal synaptosomes were preloaded with [3H]noradrenaline ([3H]NA) or [3H]D-aspartate ([3H]D-Asp) and acutely exposed to CXCL12, to NMDA or to both agonists. CXCL12, inactive on its own, facilitated the NMDA-evoked tritium release. The NMDA antagonist MK-801 abolished the NMDA/CXCL12-evoked tritium release of both radiolabelled tracers, while the CXCR4 antagonist AMD 3100 halved it, suggesting that rat hippocampal nerve endings possess presynaptic release-regulating CXCR4 receptors colocalized with NMDA receptors. Accordingly, Western blot analysis confirmed the presence of CXCR4 proteins in synaptosomal plasmamembranes. In both synaptosomal preparations, CXCL12-induced facilitation of NMDA-mediated release was dependent upon PLC-mediated src-induced events leading to mobilization of Ca2+from intraterminal IP3-sensitive stores Finally, the gp120-induced facilitation of NMDA-mediated release of [3H]NA and [3H]D-Asp was prevented by AMD 3100. We propose that CXCR4s are functionally coupled to NMDA receptors in rat hippocampal noradrenergic and glutamatergic terminals and account for the gp120-induced modulation of the NMDA-mediated central effects. The NMDA/CXCR4 cross-talk could have a role in the neuropsychiatric symptoms often observed in HIV-1 positive patients.
authors.affiliation: Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Prisco
authors.affiliation: Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy.
authors.forename: Guendalina
authors.initials: G
authors.lastname: Olivero
authors.affiliation: Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Merega
authors.affiliation: Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Bonfiglio
authors.affiliation: Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy.|Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Marchi
authors.affiliation: Department of Pharmacy, DIFAR, Pharmacology and Toxicology Section, University of Genoa, Viale Cembrano 4, 16148, Genoa, Italy. pittalug@difar.unige.it.|Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, 16132, Genoa, Italy. pittalug@difar.unige.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Pittaluga
mesh_terms: D059331:Adrenergic Neurons / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D054377:Chemokine CXCL12 / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D016202:N-Methylaspartate / Q000494:pharmacology; D009411:Nerve Endings / Q000187:drug effects / Q000502:physiology*; D011485:Protein Binding / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000819:agonists / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists / Q000502:physiology*
chemical_list: C575935:CXCL12 protein, rat; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D019718:Receptors, CXCR4; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016202:N-Methylaspartate
keywords: CXCL12; CXCR4; Glutamate; NMDA receptor; Noradrenaline; gp120