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Title: Identification of BiP as a CB1 receptor-interacting protein that fine-tunes cannabinoid signaling in the mouse brain
Author: Costas-Insua, Carlos
Moreno Guillén, Estefanía
Maroto, Irene B.
Ruiz-Calvo, Andrea
Bajo-Grañeras, Raquel
Martín-Gutiérrez, David
Diez-Alarcia, Rebeca
Vilaró, M.Teresa
Cortés, Roser
García-Font, Nuria
Martín, Ricardo
Espina, Marc
Botta, Joaquín
Ginés Padrós, Silvia
McCormick, Peter J.
Sánchez-Prieto, José
Galve-Roperh, Ismael
Mengod, Guadalupe
Urigüen, Leyle
Marsicano, Giovanni
Bellocchio, Luigi
Canela Campos, Enric I.
Casadó, Vicent
Rodríguez-Crespo, Ignacio
Guzmán, Manuel
Keywords: Neurotransmissió
Neural transmission
Issue Date: 5-Aug-2021
Publisher: The Society for Neuroscience
Abstract: 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-α. 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 BiP+/- mice supported that CB1R-BiP complexes modulate cannabinoid-evoked anxiety, one of the most frequent undesired effects of cannabis. Altogether, 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.
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It is part of: Journal of Neuroscience, 2021, vol. 41, num. 38, p. 7924-7941
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ISSN: 0270-6474
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)

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