Abstract
Glutamate is probably the most important excitatory neurotransmitter in the brain. The glutamate N-methyl-D-aspartate receptor (NMDAR) is a calcium-gated channel that coordinates with G protein-coupled receptors (GPCRs) to establish the efficiency of the synaptic transmission. Cross-regulation between these receptors requires the concerted activity of the histidine triad nucleotide-binding protein 1 (HINT1) and of the sigma receptor type 1 (σ1R). Essential brain functions like learning, memory formation and consolidation, mood and behavioral responses to exogenous stimuli depend on the activity of NMDARs. In this biological context, endocannabinoids are released to retain NMDAR activity within physiological limits. The efficacy of such control depends on HINT1/σ1R assisting in the physical coupling between cannabinoid type 1 receptors (CB1Rs) and NMDARs to dampen their activity. Subsequently, the calcium-regulated HINT1/σ1R protein tandem uncouples CB1Rs to prevent NMDAR hypofunction. Thus, early recruitment or a disproportionate cannabinoid induced response can bring about excess dampening of NMDAR activity, impeding its adequate integration with GPCR signaling. Alternatively, this control circuit can apparently be overridden in situations where bursts of NMDAR overactivity provoke convulsive syndromes. In this review we will discuss the possible relevance of the HINT1/σ1R tandem and its use by endocannabinoids to diminish NMDAR activity and their implications in psychosis/schizophrenia, as well as in NMDAR-mediated convulsive episodes.
Highlights
The glutamatergic system plays an essential role in neural signaling and as such, the ionotropic N-methyl-Daspartate receptors (NMDARs) influence the operative tone of the synapse by determining the weight assigned to the incoming signals
This review will analyze the negative control that endocannabinoids exert on NMDAR activity and its potential to reduce the incidence of convulsive syndromes like epilepsy, which are mediated by NMDAR hyperactivity, as well as their possible role in provoking NMDAR hypofunction, such as that accompanying psychosis/schizophrenia
The C terminus of NMDAR NR1 subunits is composed of C0-C2(C2’) or of C0-C1-C2(C2 ́) domains, and the NMDAR NR1 subunits that carry the C1 region bind to the C terminus of the dopamine D1 receptor [35], that of group I metabotropic glutamate receptor [36], the mu-opioid receptor (MOR) [37] and the cannabinoid type 1 receptors (CB1Rs) [25] when studied in vitro and in cell assays
Summary
The glutamatergic system plays an essential role in neural signaling and as such, the ionotropic N-methyl-Daspartate receptors (NMDARs) influence the operative tone of the synapse by determining the weight assigned to the incoming signals. NMDARs stimulate complex cellular signaling pathways, yet they exert a mutual regulation on each other’s signaling [1, 2] In this context, the endocannabinoid system, though the activation of the cannabinoid 1 receptor (CB1R), plays a very relevant role in reducing NMDAR activity [3, 4]. The endocannabinoid system, though the activation of the cannabinoid 1 receptor (CB1R), plays a very relevant role in reducing NMDAR activity [3, 4] This endogenous system could be pharmacologically manipulated to re-establish the function of dysregulated NMDARs. There are several excellent reviews on glutamate [5, 6] and endocannabinoids [7, 8] that will bring the reader up to date on what is currently known about these systems. This review will analyze the negative control that endocannabinoids exert on NMDAR activity and its potential to reduce the incidence of convulsive syndromes like epilepsy, which are mediated by NMDAR hyperactivity, as well as their possible role in provoking NMDAR hypofunction, such as that accompanying psychosis/schizophrenia
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