RT Journal Article
T1 Identification of bip as a cb1 receptor-interacting protein that fine-tunes cannabinoid signaling in the mouse brain
A1 Costas Insúa, Carlos
A1 Moreno, Estefanía
A1 Maroto Martínez, Irene Berenice
A1 Ruiz-Calvo, Andrea
A1 Bajo Grañeras, Raquel
A1 Martín-Gutiérrez, David
A1 Diez-Alarcia, Rebeca
A1 Vilaró, M. Teresa
A1 Cortés, Roser
A1 García Font, Nuria
A1 Martín Herranz, Ricardo
A1 Espina, Marc
A1 Botta, Joaquín
A1 Ginés, Silvia
A1 McCormick, Peter J.
A1 Sánchez-Prieto Borja, José
A1 Galve Roperh, Ismael
A1 Mengod, Guadalupe
A1 Urigüen, Leyre
A1 Marsicano, Giovanni
A1 Bellocchio, Luigi
A1 Canela, Enric I.
A1 Casadó, Vicent
A1 Rodríguez Crespo, José Ignacio
A1 Guzmán Pastor, Manuel
AB 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. 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.
PB SOC NEUROSCIENCE
SN 1529-2401, 0270-6474
YR 2021
FD 2021
LK https://hdl.handle.net/20.500.14352/131834
UL https://hdl.handle.net/20.500.14352/131834
LA eng
NO Costas-Insua, C., Moreno, E., Maroto, I. B., Ruiz-Calvo, A., Bajo-Grañeras, R., Martín-Gutiérrez, D., Diez-Alarcia, R., Vilaró, M. T., Cortés, R., García-Font, N., Martín, R., Espina, M., Botta, J., Ginés, S., McCormick, P. J., Sánchez-Prieto, J., Galve-Roperh, I., Mengod, G., Urigüen, L., Marsicano, G., … Guzmán, M. (2021). Identification of BiP as a CB1 Receptor-Interacting Protein That Fine-Tunes Cannabinoid Signaling in the Mouse Brain. The Journal of neuroscience : the official journal of the Society for Neuroscience, 41(38), 7924–7941. https://doi.org/10.1523/JNEUROSCI.0821-21.2021
NO 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.;
NO R.B.-G. was supported by a contract from Spanish Ministerio de Ciencia e Innovación Juan de la Cierva Program.
NO 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.
NO 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).
DS Docta Complutense
RD 26 feb 2026