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

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 in vitro, mapped interaction site within C-terminal (intracellular) domain (substrate-binding) domain-α. selectively shaped agonist-evoked signaling blocking an “alternative” Gq/11 protein-dependent module while leaving “classical” Gi/o inhibition cAMP pathway unaffected. In situ 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. SIGNIFICANCE STATEMENT 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