ArticleMolecular brain2013
HINT1 protein cooperates with cannabinoid 1 receptor to negatively regulate glutamate NMDA receptor activity.
Article in Molecular brain, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 53 citations in OpenAlex.
- The antioxidant N-acetylcysteine prevents cortical neuropathological phenotypes caused by adolescent Δ-9-tetrahydrocannabinol exposure in male rats.Translational psychiatry · 2025Article
- Cannabinoid CBACS pharmacology & translational science · 2025Article
- Recent Preclinical Evidence on Phytocannabinoids in Neurodegenerative Disorders: A Focus on Parkinson's and Alzheimer's Disease.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Cannabinoids: Role in Neurological Diseases and Psychiatric Disorders.International journal of molecular sciences · 2024Review
- Prenatal Exposure to Δ9-Tetrahydrocannabinol Affects Hippocampus-Related Cognitive Functions in the Adolescent Rat Offspring: Focus on Specific Markers of Neuroplasticity.Pharmaceutics · 2023Article
- Intracellular Molecular Targets and Signaling Pathways Involved in Antioxidative and Neuroprotective Effects of Cannabinoids in Neurodegenerative Conditions.Antioxidants (Basel, Switzerland) · 2022Review
- Molecular Targets of Cannabinoids Associated with Depression.Current medicinal chemistry · 2022Review
- An Emerging Role for Sigma-1 Receptors in the Treatment of Developmental and Epileptic Encephalopathies.International journal of molecular sciences · 2021Review
- THC-induced behavioral stereotypy in zebrafish as a model of psychosis-like behavior.Scientific reports · 2021Article
- Receptor-Dependent and Independent Regulation of Voltage-Gated CaInternational journal of molecular sciences · 2021Review
- The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets.International journal of molecular sciences · 2021Review
- Calmodulin Supports TRPA1 Channel Association with Opioid Receptors and Glutamate NMDA Receptors in the Nervous Tissue.International journal of molecular sciences · 2020Article
- The role of HINT1 in methamphetamine-induced behavioral sensitization.Psychopharmacology · 2020Article
- Neuroprotective Action of the CB1/2 Receptor Agonist, WIN 55,212-2, against DMSO but Not Phenobarbital-Induced Neurotoxicity in Immature Rats.Neurotoxicity research · 2019Article
- Neuroprotective effects of fatty acid amide hydrolase catabolic enzyme inhibition in a HIV-1 Tat model of neuroAIDS.Neuropharmacology · 2018Article
- The Sigma-1 Receptor Antagonist, S1RA, Reduces Stroke Damage, Ameliorates Post-Stroke Neurological Deficits and Suppresses the Overexpression of MMP-9.Molecular neurobiology · 2018Article
- Fenfluramine diminishes NMDA receptor-mediated seizures via its mixed activity at serotonin 5HT2A and type 1 sigma receptors.Oncotarget · 2018Article
- Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System.International journal of molecular sciences · 2018Review
- The Role of HINT1 in Methamphetamine-Induced Conditioned Place Preference.Neurotoxicity research · 2018Article
- Schizophrenia and depression, two poles of endocannabinoid system deregulation.Translational psychiatry · 2017Article
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundG protein-coupled receptors (GPCRs) are the targets of a large number of drugs currently in therapeutic use. Likewise, the glutamate ionotropic N-methyl-D-aspartate receptor (NMDAR) has been implicated in certain neurological disorders, such as neurodegeration, neuropathic pain and mood disorders, as well as psychosis and schizophrenia. Thus, there is now an important need to characterize the interactions between GPCRs and NMDARs. Indeed, these interactions can produce distinct effects, and whereas the activation of Mu-opioid receptor (MOR) increases the calcium fluxes associated to NMDARs, that of type 1 cannabinoid receptor (CNR1) antagonizes their permeation. Notably, a series of proteins interact with these receptors affecting their responses and interactions, and then emerge as novel therapeutic targets for the aforementioned pathologies.
resultsWe found that in the presence of GPCRs, the HINT1 protein influences the activity of NMDARs, whereby NMDAR activation was enhanced in CNR1+/+/HINT1-/- cortical neurons and the cannabinoid agonist WIN55,212-2 provided these cells with no protection against a NMDA insult. NMDAR activity was normalized in these cells by the lentiviral expression of HINT1, which also restored the neuroprotection mediated by cannabinoids. NMDAR activity was also enhanced in CNR1-/-/HINT1+/+ neurons, although this activity was dampened by the expression of GPCRs like the MOR, CNR1 or serotonin 1A (5HT1AR).
conclusionsThe HINT1 protein plays an essential role in the GPCR-NMDAR connection. In the absence of receptor activation, GPCRs collaborate with HINT1 proteins to negatively control NMDAR activity. When activated, most GPCRs release the control of HINT1 and NMDAR responsiveness is enhanced. However, cannabinoids that act through CNR1 maintain the negative control of HINT1 on NMDAR function and their protection against glutamate excitotoxic insult persists.
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