Identification of BiP as a CB1 receptor-interacting protein that fine-tunes cannabinoid signaling in the mouse brain
| Autor: | David Martín-Gutiérrez, Ignacio Rodríguez-Crespo, Giovanni Marsicano, Joaquin Botta, Leyre Urigüen, José Sánchez-Prieto, Marc Espina, Rebeca Diez-Alarcia, Irene B. Maroto, Carlos Costas-Insua, Nuria García-Font, Raquel Bajo-Grañeras, Peter J. McCormick, Roser Cortés, Vicent Casadó, Andrea Ruiz-Calvo, Manuel Guzmán, Enric I. Canela, M. Teresa Vilaró, Ismael Galve-Roperh, Estefanía Moreno, Silvia Ginés, Guadalupe Mengod, Luigi Bellocchio, Ricardo Martín |
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| Přispěvatelé: | Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Instituto Ramon y Cajal de Investigacion Sanitaria [Madrid, Spain] (IRYCIS), Universidad de Alcalá - University of Alcalá (UAH), University of Barcelona, University of the Basque Country/Euskal Herriko Unibertsitatea (UPV/EHU), Centro de Investigación Biomédica en Red Salud Mental [Madrid] (CIBER-SAM), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Instituto de Investigación Sanitaria del Hospital Clínico San Carlos [Madrid, Spain] (IdISSC), Queen Mary University of London (QMUL), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), INSERM, Neurocentre Magendie, U1215, Physiopathologie de la Plasticité Neuronale, F-33000 Bordeaux, France, Institut National de la Santé et de la Recherche Médicale, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Biotechnology and Biological Sciences Research Council, Ministerio de Ciencia, Innovación y Universidades, Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas (España), Biotechnology and Biological Sciences Research Council (UK), Institut National de la Santé et de la Recherche Médicale (France) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Cell signaling
Cannabinoid receptor G-protein-coupled receptor genetic structures BiP medicine.medical_treatment Biology 01 natural sciences protein-protein interaction 03 medical and health sciences Protein-protein interaction Cànnabis medicine cell signaling neurotransmission Cannabinoid Effects of cannabis 030304 developmental biology G protein-coupled receptor Cannabis Neural transmission 0303 health sciences 010405 organic chemistry General Neuroscience Neurotransmission Proteins cannabinoid 0104 chemical sciences 3. Good health Protein–protein interaction BiPG-protein-coupled receptor cAMP-dependent pathway Neurotransmissió [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] Signal transduction Neuroscience Proteïnes Intracellular Cell signalling |
| Zdroj: | Journal of Neuroscience Journal of Neuroscience, Society for Neuroscience, 2021, 41 (38), pp.7924-7941. ⟨10.1523/JNEUROSCI.0821-21.2021⟩ Addi. Archivo Digital para la Docencia y la Investigación instname Digital.CSIC. Repositorio Institucional del CSIC Dipòsit Digital de la UB Universidad de Barcelona |
| ISSN: | 0270-6474 1529-2401 |
| DOI: | 10.1523/JNEUROSCI.0821-21.2021⟩ |
| Popis: | Cannabinoids, the bioactive constituents of cannabis, exert a wide array of effects on the brain by engaging Type 1 cannabinoid receptor (CB1R). Accruing evidence supports that cannabinoid action relies on context-dependent factors, such as the biological characteristics of the target cell, suggesting that cell population-intrinsic molecular cues modulate CB1R-dependent signaling. Here, by using a yeast two-hybrid-based high-throughput screening, we identified BiP as a potential CB1R-interacting protein. We next found that CB1R and BiP interact specifically in vitro, and mapped the interaction site within the CB1R C-terminal (intracellular) domain and the BiP C-terminal (substrate-binding) domain-a. BiP selectively shaped agonist-evoked CB1R signaling by blocking an "alternative" Gq/11 protein-dependent signaling module while leaving the "classical" Gi/o protein-dependent inhibition of the cAMP pathway unaffected. In situ proximity ligation assays conducted on brain samples from various genetic mouse models of conditional loss or gain of CB1R expression allowed to map CB1R-BiP complexes selectively on terminals of GABAergic neurons. Behavioral studies using cannabinoid- treated male BiP1/2 mice supported that CB1R-BiP complexes modulate cannabinoid-evoked anxiety, one of the most frequent undesired effects of cannabis. Together, by identifying BiP as a CB1R-interacting protein that controls receptor function in a signaling pathway- and neuron population-selective manner, our findings may help to understand the striking context-dependent actions of cannabis in the brain. This work was supported by Spanish Ministerio de Ciencia e Innovación Grants RTI2018-095311-B-I00 to M.G., SAF-2017-87629-R to E.I.C. and V.C., PID2019-106404RB-I00 to L.U., BFU 2017-83292-R to J.S.-P., and RTI2018-094374-B-I00 to S.G.; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas Grant PI2018/01 to M.G., S.G., and G. Mengod; and UK Research and Innovation Biotechnology and Biological Sciences Research Council Grant BB/R006946/1 to P.J.M., L.B., and G. Marsicano were supported by Institut National de la Santé et de la Recherche Médicale. C.C.-I. and I.B.M. were supported by contracts from Spanish Ministerio de Universidades (Formación de Profesorado Universitario Program, references FPU16/02593 and FPU15/01833, respectively). R.B.-G. was supported by a contract from Spanish Ministerio de Ciencia e Innovación Juan de la Cierva Program. |
| Databáze: | OpenAIRE |
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