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Control of glutamate release by complexes of adenosine and cannabinoid receptors

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dc.contributor.authorKöfalvi, Attila
dc.contributor.authorMoreno, Estefanía
dc.contributor.authorCordomí, Arnau
dc.contributor.authorCai, Ning-Sheng
dc.contributor.authorFernández-Dueñas, Victor
dc.contributor.authorFerreira, Samira G.
dc.contributor.authorGuixà-González, Ramón
dc.contributor.authorSánchez-Soto, Marta
dc.contributor.authorYano, Hideaki
dc.contributor.authorCasadó-Anguera, Verònica
dc.contributor.authorCunha, Rodrigo A.
dc.contributor.authorSebastião, Ana M
dc.contributor.authorCiruela, Francisco
dc.contributor.authorPardo, Leonardo
dc.contributor.authorCasadó, Vicent
dc.contributor.authorFerré, Sergi
dc.date.accessioned2022-12-06T14:34:57Z
dc.date.available2022-12-06T14:34:57Z
dc.date.issued2020
dc.description© The Author(s). 2020 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.pt_PT
dc.description.abstractBackground: It has been hypothesized that heteromers of adenosine A2A receptors (A2AR) and cannabinoid CB1 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. Results: 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 A1 receptors or dopamine D2 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. Conclusions: 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.pt_PT
dc.description.sponsorshipWork supported with the intramural funds of the National Institute on Drug Abuse, “Ministerio de Ciencia, Innovación y Universidades-Agencia Estatal de Investigación/FEDER” (SAF2015-74627-JIN, SAF2016-77830-R, SAF2017-87349-R) and ISCIII/FEDER (PIE14/00034), the Catalan government (2017 SGR 1604), “Fundació la Marató de TV3” (20152031), FWO (SBO-140028), “Fundação para a Ciência e a Tecnologia” (PTDC/DTP-FTO/3346/2014 and PTDC/MED-NEU/31274/2017), FEDER (QREN) through “Programa Operacional Factores de Competitividade” (COMPETE 2020, POCI-01-0145-FEDER-007440, CENTRO-01-0145-FEDER-000012-N2323P30, and UID/NEU/04539/2019), and through “Programa Mais Centro” (CENTRO-01-0246-FEDER-000010 and CENTRO-07-ST24-FEDER-002006).pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationBMC Biol. 2020 Jan 23;18(1):9pt_PT
dc.identifier.doi10.1186/s12915-020-0739-0pt_PT
dc.identifier.eissn1741-7007
dc.identifier.urihttp://hdl.handle.net/10451/55356
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherSpringer Naturept_PT
dc.relationPOCI-01-0145-FEDER-007440pt_PT
dc.relationSynaptic mechanisms involved in the brain cannabinoid actions and their modulation by adenosine receptors: implications for memory and mood control
dc.relationAdenosine A2A receptors as triggers of memory dysfunction in Alzheimer?s disease: mechanisms and therapeutic propects
dc.relationCENTRO-01-0246-FEDER-000010pt_PT
dc.relationCENTRO-07-ST24-FEDER-002006pt_PT
dc.relationCNC. IBILI
dc.relation.publisherversionhttps://bmcbiol.biomedcentral.com/pt_PT
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/pt_PT
dc.subjectAdenosine A2A receptorpt_PT
dc.subjectAdenylyl cyclasept_PT
dc.subjectCannabinoid CB1 receptorpt_PT
dc.subjectGPCR heteromerspt_PT
dc.subjectGlutamate transmissionpt_PT
dc.subjectStriatumpt_PT
dc.titleControl of glutamate release by complexes of adenosine and cannabinoid receptorspt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardNumberPTDC/DTP-FTO/3346/2014
oaire.awardNumberPTDC/MED-NEU/31274/2017
oaire.awardNumberUID/NEU/04539/2019
oaire.awardTitleSynaptic mechanisms involved in the brain cannabinoid actions and their modulation by adenosine receptors: implications for memory and mood control
oaire.awardTitleAdenosine A2A receptors as triggers of memory dysfunction in Alzheimer?s disease: mechanisms and therapeutic propects
oaire.awardTitleCNC. IBILI
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FDTP-FTO%2F3346%2F2014/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/9471 - RIDTI/PTDC%2FMED-NEU%2F31274%2F2017/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UID%2FNEU%2F04539%2F2019/PT
oaire.citation.issue1pt_PT
oaire.citation.titleBMC Biologypt_PT
oaire.citation.volume18pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream9471 - RIDTI
oaire.fundingStream6817 - DCRRNI ID
person.familyNameSebastião
person.givenNameAna M
person.identifier.ciencia-idF112-55E8-E37E
person.identifier.orcid0000-0001-9030-6115
person.identifier.scopus-author-id7004409879
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsopenAccesspt_PT
rcaap.typearticlept_PT
relation.isAuthorOfPublication304abd7f-071b-4447-a8a3-4aa5f0547141
relation.isAuthorOfPublication.latestForDiscovery304abd7f-071b-4447-a8a3-4aa5f0547141
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