Research Papers: Pathology:

The ON:OFF switch, σ1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: Implications in neurological disorders

María Rodríguez-Muñoz _, Elsa Cortés-Montero, Andrea Pozo-Rodrigálvarez, Pilar Sánchez-Blázquez and Javier Garzón-Niño

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Oncotarget. 2015; 6:35458-35477. https://doi.org/10.18632/oncotarget.6064

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María Rodríguez-Muñoz1, Elsa Cortés-Montero1, Andrea Pozo-Rodrigálvarez1, Pilar Sánchez-Blázquez1 and Javier Garzón-Niño1

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

Correspondence to:

Javier Garzón-Niño, email:

Keywords: σ1R, HINT1 protein, cannabinoid CB1 receptor, neurological disorders, mu-opioid receptor, Pathology Section

Received: June 30, 2015 Accepted: September 23, 2015 Published: October 10, 2015


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.

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