The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: Implications in neurological disorders
| Autor: | Pilar Sánchez-Blázquez, Andrea Pozo-Rodrigálvarez, Elsa Cortés-Montero, María Rodríguez-Muñoz, Javier Garzón-Niño |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_treatment neurological disorders Molecular Sequence Data Excitotoxicity Nerve Tissue Proteins Biology medicine.disease_cause Bioinformatics Receptors N-Methyl-D-Aspartate Rhodopsin-like receptors Receptors G-Protein-Coupled Mice Pathology Section mental disorders medicine Animals Receptors sigma Amino Acid Sequence Receptor HINT1 protein G protein-coupled receptor Mice Knockout musculoskeletal neural and ocular physiology Glutamate receptor σ1R Receptor Cross-Talk Research Paper: Pathology Cell biology nervous system Oncology cannabinoid CB1 receptor mu-opioid receptor NMDA receptor Calcium Cannabinoid Nervous System Diseases biological phenomena cell phenomena and immunity Signal transduction psychological phenomena and processes Signal Transduction |
| Zdroj: | Oncotarget |
| ISSN: | 1949-2553 |
| DOI: | 10.18632/oncotarget.6064 |
| Popis: | In the brain, the histidine triad nucleotide-binding protein 1 (HINT1) and sigma 1 receptors (σ1Rs) coordinate the activity of certain G-protein coupled receptors (GPCRs) with that of glutamate N-methyl-D-aspartate receptors (NMDARs). To determine the role of HINT1-σ1R in the plasticity of GPCR-NMDAR interactions, substances acting at MOR, cannabinoid CB1 receptor, NMDAR and σ1R were injected into mice, and their effects were evaluated through in vivo, ex vivo, and in vitro assays. It was observed that HINT1 protein binds to GPCRs and NMDAR NR1 subunits in a calcium-independent manner, whereas σ1R binding to these proteins increases in the presence of calcium. In this scenario, σ1R agonists keep HINT1 at the GPCR and stimulate GPCR-NMDAR interaction, whereas σ1R antagonists transfer HINT1 to NR1 subunits and disengage both receptors. This regulation is lost in σ1R-/- mice, where HINT1 proteins mostly associate with NMDARs, and GPCRs are physically and functionally disconnected from NMDARs. In HINT1-/- mice, ischemia produces low NMDAR-mediated brain damage, suggesting that several different GPCRs enhance glutamate excitotoxicity via HINT1-σ1R. Thus, several GPCRs associate with NMDARs by a dynamic process under the physiological control of HINT1 proteins and σ1Rs. The NMDAR-HINT1-σ1R complex deserves attention because it offers new therapeutic opportunities. |
| Databáze: | OpenAIRE |
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