N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors

Abstract Background The cannabinoid CB2 receptor (CB2R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of c...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Rafael Rivas-Santisteban, Alejandro Lillo, Jaume Lillo, Joan-Biel Rebassa, Joan S. Contestí, Carlos A. Saura, Rafael Franco, Gemma Navarro
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Alzheimer’s disease Neuroprotection G-protein-coupled receptors Excitotoxicity Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
Acceso en línea:	https://doaj.org/article/0254e2d26c33408e83ebdd64aef88946
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:0254e2d26c33408e83ebdd64aef88946
record_format	dspace
spelling	oai:doaj.org-article:0254e2d26c33408e83ebdd64aef889462021-11-14T12:39:09ZN-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors10.1186/s13195-021-00920-61758-9193https://doaj.org/article/0254e2d26c33408e83ebdd64aef889462021-11-01T00:00:00Zhttps://doi.org/10.1186/s13195-021-00920-6https://doaj.org/toc/1758-9193Abstract Background The cannabinoid CB2 receptor (CB2R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer’s disease patients and with the aim of finding neuromodulators of their actions that could provide benefits in dementia, we hypothesized that cannabinoids could modulate NMDA function. Methods Immunocytochemistry was used to analyze the colocalization between CB2 and NMDA receptors; bioluminescence resonance energy transfer was used to detect CB2-NMDA receptor complexes. Calcium and cAMP determination, mitogen-activated protein kinase (MAPK) pathway activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify CB2-NMDA heteromer expression in mouse primary cultures and in the brain of APPSw/Ind transgenic mice, an Alzheimer’s disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP). Results In a heterologous system, we identified CB2-NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon-γ. CB2R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that in brain slices and in primary cells (microglia or neurons) from APPSw/Ind mice, there was a marked overexpression of macromolecular CB2-NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input by cannabinoids. Conclusions The results indicate a negative cross-talk in CB2-NMDA complexes signaling. The expression of the CB2-NMDA receptor heteromers increases in both microglia and neurons from the APPSw/Ind transgenic mice, compared with levels in samples from age-matched control mice.Rafael Rivas-SantistebanAlejandro LilloJaume LilloJoan-Biel RebassaJoan S. ContestíCarlos A. SauraRafael FrancoGemma NavarroBMCarticleAlzheimer’s diseaseNeuroprotectionG-protein-coupled receptorsExcitotoxicityNeurosciences. Biological psychiatry. NeuropsychiatryRC321-571Neurology. Diseases of the nervous systemRC346-429ENAlzheimer’s Research & Therapy, Vol 13, Iss 1, Pp 1-15 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Alzheimer’s disease Neuroprotection G-protein-coupled receptors Excitotoxicity Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429
spellingShingle	Alzheimer’s disease Neuroprotection G-protein-coupled receptors Excitotoxicity Neurosciences. Biological psychiatry. Neuropsychiatry RC321-571 Neurology. Diseases of the nervous system RC346-429 Rafael Rivas-Santisteban Alejandro Lillo Jaume Lillo Joan-Biel Rebassa Joan S. Contestí Carlos A. Saura Rafael Franco Gemma Navarro N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors
description	Abstract Background The cannabinoid CB2 receptor (CB2R), which is a target to afford neuroprotection, and N-methyl-D-aspartate (NMDA) ionotropic glutamate receptors, which are key in mediating excitatory neurotransmission, are expressed in both neurons and glia. As NMDA receptors are the target of current medication in Alzheimer’s disease patients and with the aim of finding neuromodulators of their actions that could provide benefits in dementia, we hypothesized that cannabinoids could modulate NMDA function. Methods Immunocytochemistry was used to analyze the colocalization between CB2 and NMDA receptors; bioluminescence resonance energy transfer was used to detect CB2-NMDA receptor complexes. Calcium and cAMP determination, mitogen-activated protein kinase (MAPK) pathway activation, and label-free assays were performed to characterize signaling in homologous and heterologous systems. Proximity ligation assays were used to quantify CB2-NMDA heteromer expression in mouse primary cultures and in the brain of APPSw/Ind transgenic mice, an Alzheimer’s disease model expressing the Indiana and Swedish mutated version of the human amyloid precursor protein (APP). Results In a heterologous system, we identified CB2-NMDA complexes with a particular heteromer print consisting of impairment by cannabinoids of NMDA receptor function. The print was detected in activated primary microglia treated with lipopolysaccharide and interferon-γ. CB2R activation blunted NMDA receptor-mediated signaling in primary hippocampal neurons from APPSw/Ind mice. Furthermore, imaging studies showed that in brain slices and in primary cells (microglia or neurons) from APPSw/Ind mice, there was a marked overexpression of macromolecular CB2-NMDA receptor complexes thus becoming a tool to modulate excessive glutamate input by cannabinoids. Conclusions The results indicate a negative cross-talk in CB2-NMDA complexes signaling. The expression of the CB2-NMDA receptor heteromers increases in both microglia and neurons from the APPSw/Ind transgenic mice, compared with levels in samples from age-matched control mice.
format	article
author	Rafael Rivas-Santisteban Alejandro Lillo Jaume Lillo Joan-Biel Rebassa Joan S. Contestí Carlos A. Saura Rafael Franco Gemma Navarro
author_facet	Rafael Rivas-Santisteban Alejandro Lillo Jaume Lillo Joan-Biel Rebassa Joan S. Contestí Carlos A. Saura Rafael Franco Gemma Navarro
author_sort	Rafael Rivas-Santisteban
title	N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors
title_short	N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors
title_full	N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors
title_fullStr	N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors
title_full_unstemmed	N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors
title_sort	n-methyl-d-aspartate (nmda) and cannabinoid cb2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial nmda receptors
publisher	BMC
publishDate	2021
url	https://doaj.org/article/0254e2d26c33408e83ebdd64aef88946
work_keys_str_mv	AT rafaelrivassantisteban nmethyldaspartatenmdaandcannabinoidcb2receptorsformfunctionalcomplexesincellsofthecentralnervoussysteminsightsintothetherapeuticpotentialofneuronalandmicroglialnmdareceptors AT alejandrolillo nmethyldaspartatenmdaandcannabinoidcb2receptorsformfunctionalcomplexesincellsofthecentralnervoussysteminsightsintothetherapeuticpotentialofneuronalandmicroglialnmdareceptors AT jaumelillo nmethyldaspartatenmdaandcannabinoidcb2receptorsformfunctionalcomplexesincellsofthecentralnervoussysteminsightsintothetherapeuticpotentialofneuronalandmicroglialnmdareceptors AT joanbielrebassa nmethyldaspartatenmdaandcannabinoidcb2receptorsformfunctionalcomplexesincellsofthecentralnervoussysteminsightsintothetherapeuticpotentialofneuronalandmicroglialnmdareceptors AT joanscontesti nmethyldaspartatenmdaandcannabinoidcb2receptorsformfunctionalcomplexesincellsofthecentralnervoussysteminsightsintothetherapeuticpotentialofneuronalandmicroglialnmdareceptors AT carlosasaura nmethyldaspartatenmdaandcannabinoidcb2receptorsformfunctionalcomplexesincellsofthecentralnervoussysteminsightsintothetherapeuticpotentialofneuronalandmicroglialnmdareceptors AT rafaelfranco nmethyldaspartatenmdaandcannabinoidcb2receptorsformfunctionalcomplexesincellsofthecentralnervoussysteminsightsintothetherapeuticpotentialofneuronalandmicroglialnmdareceptors AT gemmanavarro nmethyldaspartatenmdaandcannabinoidcb2receptorsformfunctionalcomplexesincellsofthecentralnervoussysteminsightsintothetherapeuticpotentialofneuronalandmicroglialnmdareceptors
_version_	1718429085724573696

N-Methyl-D-aspartate (NMDA) and cannabinoid CB2 receptors form functional complexes in cells of the central nervous system: insights into the therapeutic potential of neuronal and microglial NMDA receptors

Ejemplares similares