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

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

doi:10.18632/oncotarget.6064

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.

Highlights

The prolific investigation of psychosis/schizophrenia and depression suggests that both G-protein coupled receptors (GPCRs) and glutamate N-methyl-D-aspartate receptors (NMDARs) participate in the pathophysiology of these mental illnesses; the hierarchy of these changes is still a matter of debate
Using bimolecular fluorescence complementation (BiFC) in living cells, we demonstrated that as well as the mu-opioid receptor (MOR), histidine triad nucleotide-binding protein 1 (HINT1) and σ1R can associate with the cannabinoid cannabinoid receptor 1 (CB1), dopamine D1 and D2, serotonin 1A and 2A, and metabotropic glutamate 2 and 5 receptors
To confirm and extend the hypothesis that the σ1R regulates the swapping of HINT1 between GPCRs and NMDARs, we studied the effect of another compound that increases morphine analgesia and has been classified as an antagonist of the σ1R

Summary

INTRODUCTION

The prolific investigation of psychosis/schizophrenia and depression suggests that both G-protein coupled receptors (GPCRs) and glutamate N-methyl-D-aspartate receptors (NMDARs) participate in the pathophysiology of these mental illnesses; the hierarchy of these changes is still a matter of debate. NMDARs, by influencing the cellular impact of signals that are originated at GPCRs, would play an essential role in neuronal plasticity, development, differentiation, learning, and memory consolidation. NMDARs functionally recruit the negative control of certain GPCRs, such as the cannabinoid CB1, to prevent the risk of excitotoxicity [6]. In this context, the cellular impact of endocannabinoids on this glutamate ionotropic receptor is under regulation; the calcium sensor σ1R [7] associates with the CB1-NMDAR complex and, when calcium levels are reduced, antagonists of σ1Rs disrupt the CB1-NMDAR association to prevent endocannabinoids from producing the hypofunction of NMDARs [8]. In vulnerable subjects with a defect in this www.impactjournals.com/oncotarget

RESULTS

DISCUSSION

MATERIALS AND METHODS