Cannabinoid receptors couple to NMDA receptors to reduce the production of NO and the mobilization of zinc induced by glutamate

Antioxid Redox Signal. 2013 Nov 20;19(15):1766-82. doi: 10.1089/ars.2012.5100. Epub 2013 Jun 1.

Abstract

Aims: 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.

Innovation: 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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2 / metabolism
  • Cannabinoids / pharmacology
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Glutamic Acid / metabolism*
  • Glutamic Acid / pharmacology
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins / chemistry
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nervous System / metabolism
  • Nitric Oxide / biosynthesis*
  • Nitric Oxide Synthase Type I / metabolism
  • Protein Binding
  • Protein Interaction Domains and Motifs
  • Protein Kinase C / metabolism
  • Receptor, Cannabinoid, CB1 / metabolism
  • Receptors, Cannabinoid / chemistry
  • Receptors, Cannabinoid / metabolism*
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / chemistry
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction
  • Zinc / metabolism*

Substances

  • Cannabinoids
  • Gprin1 protein, mouse
  • Hint1 protein, mouse
  • Nerve Tissue Proteins
  • Receptor, Cannabinoid, CB1
  • Receptors, Cannabinoid
  • Receptors, N-Methyl-D-Aspartate
  • Nitric Oxide
  • Glutamic Acid
  • Nitric Oxide Synthase Type I
  • Cyclic AMP-Dependent Protein Kinases
  • Protein Kinase C
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Zinc