Identification of BiP as a CB1 Receptor-Interacting Protein That Fine-Tunes Cannabinoid Signaling in the Mouse Brain

• DOI: 10.1523/jneurosci.0821-21.2021
• Publication Date: 2021-08-05T17:50:22Z
• Authors: Carlos Costas-Insua; Estefanía Moreno; Irene B. Maroto; Andrea Ruiz-Calvo; Raquel Bajo-Grañeras; David Martín-Guti...; Rebeca Diez-Alarcia; M. Teresa Vilaró; Roser Cortés; Nuria García-Font; Ricardo Martín; Marc Espina; Joaquín Botta; Silvia Ginés; Peter J. McCormick; José Sánchez-Prieto; Ismael Galve-Roperh; Guadalupe Mengod; Leyre Urigüen; Giovanni Marsicano; Luigi Bellocchio; Enric I. Canela; Vicent Casadó; Ignacio Rodríguez...; Manuel Guzmán
• Keywords: Cell signaling; G-protein-coupled receptor; BiP; protein-protein interaction; Mice; 03 medical and health sciences; Protein-protein interaction; Receptor, Cannabinoid, CB1; Cànnabis; cell signaling; Animals; Humans; neurotransmission; GABAergic Neurons; Cannabinoid; Endoplasmic Reticulum Chaperone BiP; Research Articles; Heat-Shock Proteins; Cannabis; Neural transmission; Mice, Knockout; 0303 health sciences; Cannabinoids; Neurotransmission; Proteins; Brain; cannabinoid; Protein–protein interaction; protein–protein interaction; HEK293 Cells; BiPG-protein-coupled receptor; Neurotransmissió; [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]; Proteïnes; Cell signalling; Signal Transduction

Cannabinoids, the bioactive constituents of cannabis, exert a wide array effects on brain by engaging Type 1 cannabinoid receptor (CB₁R). Accruing evidence supports that action relies context-dependent factors, such as biological characteristics target cell, suggesting cell population-intrinsic molecular cues modulate CB₁R-dependent signaling. Here, using yeast two-hybrid-based high-throughput screening, we identified BiP potential CB₁R-interacting protein. We next found CB₁R and interact specifically <i>in vitro</i>, mapped interaction site within <i>C</i>-terminal (intracellular) domain (substrate-binding) domain-α. selectively shaped agonist-evoked signaling blocking an "alternative" G_q/11 protein-dependent module while leaving "classical" G_i/o inhibition cAMP pathway unaffected. <i>In situ</i> proximity ligation assays conducted samples from various genetic mouse models conditional loss or gain expression allowed to map CB₁R-BiP complexes terminals GABAergic neurons. Behavioral studies cannabinoid-treated male BiP^+/− mice supported cannabinoid-evoked anxiety, one most frequent undesired cannabis. Together, identifying protein controls function in pathway- neuron population-selective manner, our findings may help understand striking actions cannabis brain. <b>SIGNIFICANCE STATEMENT</b> Cannabis use is increasing worldwide, so innovative aimed its complex mechanism neurobiological are warranted. CB₁ (CB₁R), primary interacts with intracellular called BiP. The between occurs (inhibitory) neurons, induces remarkable shift CB₁R-associated profile. support act fine-tuners use. Our open new conceptual framework pharmacological