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The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: implications in neurological disorders.
Oncotarget. 2015 Nov 03; 6(34):35458-77.O

Abstract

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.

Authors+Show Affiliations

Department of Molecular, Cellular and Developmental Neurobiology, Laboratory of Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.Department of Molecular, Cellular and Developmental Neurobiology, Laboratory of Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.Department of Molecular, Cellular and Developmental Neurobiology, Laboratory of Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.Department of Molecular, Cellular and Developmental Neurobiology, Laboratory of Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.Department of Molecular, Cellular and Developmental Neurobiology, Laboratory of Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26461475

Citation

Rodríguez-Muñoz, María, et al. "The ON:OFF Switch, σ1R-HINT1 Protein, Controls GPCR-NMDA Receptor Cross-regulation: Implications in Neurological Disorders." Oncotarget, vol. 6, no. 34, 2015, pp. 35458-77.
Rodríguez-Muñoz M, Cortés-Montero E, Pozo-Rodrigálvarez A, et al. The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: implications in neurological disorders. Oncotarget. 2015;6(34):35458-77.
Rodríguez-Muñoz, M., Cortés-Montero, E., Pozo-Rodrigálvarez, A., Sánchez-Blázquez, P., & Garzón-Niño, J. (2015). The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: implications in neurological disorders. Oncotarget, 6(34), 35458-77. https://doi.org/10.18632/oncotarget.6064
Rodríguez-Muñoz M, et al. The ON:OFF Switch, σ1R-HINT1 Protein, Controls GPCR-NMDA Receptor Cross-regulation: Implications in Neurological Disorders. Oncotarget. 2015 Nov 3;6(34):35458-77. PubMed PMID: 26461475.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: implications in neurological disorders. AU - Rodríguez-Muñoz,María, AU - Cortés-Montero,Elsa, AU - Pozo-Rodrigálvarez,Andrea, AU - Sánchez-Blázquez,Pilar, AU - Garzón-Niño,Javier, PY - 2015/06/30/received PY - 2015/09/23/accepted PY - 2015/10/14/entrez PY - 2015/10/16/pubmed PY - 2016/10/21/medline KW - HINT1 protein KW - Pathology Section KW - cannabinoid CB1 receptor KW - mu-opioid receptor KW - neurological disorders KW - σ1R SP - 35458 EP - 77 JF - Oncotarget JO - Oncotarget VL - 6 IS - 34 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/26461475/The_ON:OFF_switch_σ1R_HINT1_protein_controls_GPCR_NMDA_receptor_cross_regulation:_implications_in_neurological_disorders_ L2 - https://www.oncotarget.com/lookup/doi/10.18632/oncotarget.6064 DB - PRIME DP - Unbound Medicine ER -