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| Home > Articles > Published articles > Control of glutamate release by complexes of adenosine and cannabinoid receptors |
(Universitat de Barcelona. Departament de Bioquímica i Biologia Molecular) (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional) (Universitat de Barcelona. Institut de Neurociències) (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional) (Universitat de Barcelona. Departament de Bioquímica i Biologia Molecular) (Universitat de Barcelona. Institut de Neurociències) (Universitat Autònoma de Barcelona. Laboratori de Medicina Computacional) (Universitat de Barcelona. Departament de Bioquímica i Biologia Molecular) (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
| Date: | 2020 |
| Abstract: | It has been hypothesized that heteromers of adenosine A receptors (A2AR) and cannabinoid CB receptors (CB1R) localized in glutamatergic nerve terminals mediate the integration of adenosine and endocannabinoid signaling involved in the modulation of striatal excitatory neurotransmission. Previous studies have demonstrated the existence of A2AR-CB1R heteromers in artificial cell systems. A dependence of A2AR signaling for the Gi protein-mediated CB1R signaling was described as one of its main biochemical characteristics. However, recent studies have questioned the localization of functionally significant A2AR-CB1R heteromers in striatal glutamatergic terminals. Using a peptide-interfering approach combined with biophysical and biochemical techniques in mammalian transfected cells and computational modeling, we could establish a tetrameric quaternary structure of the A2AR-CB1R heterotetramer. This quaternary structure was different to the also tetrameric structure of heteromers of A2AR with adenosine A receptors or dopamine D receptors, with different heteromeric or homomeric interfaces. The specific quaternary structure of the A2A-CB1R, which depended on intermolecular interactions involving the long C-terminus of the A2AR, determined a significant A2AR and Gs protein-mediated constitutive activation of adenylyl cyclase. Using heteromer-interfering peptides in experiments with striatal glutamatergic terminals, we could then demonstrate the presence of functionally significant A2AR-CB1R heteromers with the same biochemical characteristics of those studied in mammalian transfected cells. First, either an A2AR agonist or an A2AR antagonist allosterically counteracted Gi-mediated CB1R agonist-induced inhibition of depolarization-induced glutamate release. Second, co-application of both an A2AR agonist and an antagonist cancelled each other effects. Finally, a CB1R agonist inhibited glutamate release dependent on a constitutive activation of A2AR by a canonical Gs-Gi antagonistic interaction at the adenylyl cyclase level. We demonstrate that the well-established cannabinoid-induced inhibition of striatal glutamate release can mostly be explained by a CB1R-mediated counteraction of the A2AR-mediated constitutive activation of adenylyl cyclase in the A2AR-CB1R heteromer. |
| Grants: | Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1604 Ministerio de Ciencia e Innovación SAF2015-74627-JIN Ministerio de Ciencia e Innovación SAF2016-77830-R Ministerio de Ciencia e Innovación SAF2017-87349-R Instituto de Salud Carlos III PIE14/00034 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Subject: | Adenosine A receptor ; Cannabinoid CB receptor ; GPCR heteromers ; Adenylyl cyclase ; Glutamate transmission ; Striatum |
| Published in: | BMC biology, Vol. 18 (january 2020) , ISSN 1741-7007 |
