| First Author | Rodríguez-Muñoz M | Year | 2015 |
| Journal | Oncotarget | Volume | 6 |
| Issue | 34 | Pages | 35458-77 |
| PubMed ID | 26461475 | Mgi Jnum | J:315564 |
| Mgi Id | MGI:6829249 | Doi | 10.18632/oncotarget.6064 |
| Citation | Rodriguez-Munoz M, et al. (2015) The ON:OFF switch, sigma1R-HINT1 protein, controls GPCR-NMDA receptor cross-regulation: implications in neurological disorders. Oncotarget 6(34):35458-77 |
| abstractText | In the brain, the histidine triad nucleotide-binding protein 1 (HINT1) and sigma 1 receptors (sigma1Rs) 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-sigma1R in the plasticity of GPCR-NMDAR interactions, substances acting at MOR, cannabinoid CB1 receptor, NMDAR and sigma1R 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 sigma1R binding to these proteins increases in the presence of calcium. In this scenario, sigma1R agonists keep HINT1 at the GPCR and stimulate GPCR-NMDAR interaction, whereas sigma1R antagonists transfer HINT1 to NR1 subunits and disengage both receptors. This regulation is lost in sigma1R-/- 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-sigma1R. Thus, several GPCRs associate with NMDARs by a dynamic process under the physiological control of HINT1 proteins and sigma1Rs. The NMDAR-HINT1-sigma1R complex deserves attention because it offers new therapeutic opportunities. |
