Endocannabinoid control of glutamate NMDA receptors: the therapeutic potential and consequences of dysfunction

María Rodríguez-Muñoz _, Pilar Sánchez-Blázquez, Manuel Merlos and Javier Garzón-Niño

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Oncotarget. 2016; 7:55840-55862. https://doi.org/10.18632/oncotarget.10095

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María Rodríguez-Muñoz1, Pilar Sánchez-Blázquez1, Manuel Merlos2 and Javier Garzón-Niño1

1 Department of Molecular, Cellular and Developmental Neurobiology, Laboratory of Neuropharmacology, Instituto Cajal, Consejo Superior de Investigaciones Científicas (CSIC), Madrid, Spain

2 Drug Discovery & Preclinical Development, Esteve, Barcelona, Spain

Correspondence to:

María Rodríguez-Muñoz, email:

Keywords: σ1R; HINT1 protein; GPCR-NMDAR coordination; convulsive disorders; mood disorders

Received: January 22, 2016 Accepted: June 06, 2016 Published: June 15, 2016


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.

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