title: Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate.
abstract: OBJECTIVE
  Overactivation of glutamate N-methyl-D-aspartate receptor (NMDAR) increases the cytosolic concentrations of calcium and zinc, which significantly contributes to neural death. Since cannabinoids prevent the NMDAR-mediated increase in cytosolic calcium, we investigated whether they also control the rise of potentially toxic free zinc ions, as well as the processes implicated in this phenomenon.
  
  
  RESULTS
  The cannabinoid receptors type 1 (CNR1) and NMDARs are cross-regulated in different regions of the nervous system. Cannabinoids abrogated the stimulation of the nitric oxide-zinc pathway by NMDAR, an effect that required the histidine triad nucleotide-binding protein 1 (HINT1). Conversely, NMDAR antagonism reduced the analgesia promoted by the CNR1 agonist WIN55,212-2 and impaired its capacity to internalize CNR1s. At the cell surface, CNR1s co-immunoprecipitated with the NR1 subunits of NMDARs, an association that diminished after the administration of NMDA in vivo or as a consequence of neuropathic overactivation of NMDARs, both situations in which cannabinoids do not control NMDAR activity. Under these circumstances, inhibition of protein kinase A (PKA) restored the association between CNR1s and NR1 subunits, and cannabinoids regained control over NMDAR activity. Notably, CNR1 and NR1 associated poorly in HINT1(-/-) mice, in which there was little cross-regulation between these receptors.
  
  
  METHODS
  The CNR1 can regulate NMDAR function when the receptor is coupled to HINT1. Thus, internalization of CNR1s drives the co-internalization of the NR1 subunits, neutralizing the overactivation of NMDARs.
  
  
  CONCLUSIONS
  Cannabinoids require the HINT1 protein to counteract the toxic effects of NMDAR-mediated NO production and zinc release. This study situates the HINT1 protein at the forefront of cannabinoid protection against NMDAR-mediated brain damage.
authors.affiliation: Department of Neuropharmacology, Cajal Institute, Consejo Superior de Investigaciones Científicas (CSIC) , Madrid, Spain .
authors.forename: Pilar
authors.initials: P
authors.lastname: Sánchez-Blázquez
authors.forename: María
authors.initials: M
authors.lastname: Rodríguez-Muñoz
authors.forename: Ana
authors.initials: A
authors.lastname: Vicente-Sánchez
authors.forename: Javier
authors.initials: J
authors.lastname: Garzón
mesh_terms: D000818:Animals; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002186:Cannabinoids / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009420:Nervous System / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011493:Protein Kinase C / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000737:chemistry / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction; D015032:Zinc / Q000378:metabolism*
chemical_list: D002186:Cannabinoids; C121673:Gprin1 protein, mouse; C489275:Hint1 protein, mouse; D009419:Nerve Tissue Proteins; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D016194:Receptors, N-Methyl-D-Aspartate; D009569:Nitric Oxide; D018698:Glutamic Acid; D052248:Nitric Oxide Synthase Type I; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D015032:Zinc