Likewise, under different cellular settings, CB 1R can signal through other G-protein families, such as G q/11 and G s ( Lauckner et al., 2005 Priestley et al., 2017). For example, CB 1R couples to the inhibitory family of heterotrimeric G-proteins (G i/o), but its expression and signaling efficacy differ remarkably between excitatory and inhibitory neurons ( Steindel et al., 2013), which could explain, at least in part, the widely reported biphasic effects elicited by THC and other CB 1R agonists ( Bellocchio et al., 2010 Rey et al., 2012 Mechoulam and Parker, 2013). The precise molecular mechanism of CB 1R action remains unsolved. It mediates a large number of pharmacological effects of THC, and, on binding endocannabinoids (anandamide and 2-arachidonoylglycerol), participates in the physiological control of multiple processes, such as motor behavior, learning and memory, fear and anxiety, pain, food intake, and energy metabolism ( Piomelli, 2003 Mechoulam et al., 2014). CB 1R is one of the most abundant GPCRs in the mammalian brain ( Katona and Freund, 2008 Pertwee et al., 2010 Dudok et al., 2015). This compound engages and activates two specific G-protein-coupled receptors (GPCRs), designated as cannabinoid CB 1 receptor (CB 1R) and cannabinoid CB 2 receptor (CB 2R) ( Pertwee et al., 2010). Both the therapeutic and the adverse effects of cannabis are mostly attributed to a single molecule, Δ 9-tetrahydrocannabinol (THC) ( Mechoulam et al., 2014). During the last decades, there has been a strong renaissance in the study of the molecular and pharmacological bases of cannabinoid action and, in concert, many countries have approved the use of cannabinoid-based medicines and standardized preparations of medicinal cannabis ( Hill, 2015 Abrams, 2018). have been used by humankind for millennia. Preparations of the hemp plant Cannabis sativa L. Our findings open a new conceptual framework to understand the striking context-dependent pharmacological actions of cannabis in the brain. Behavioral studies conducted in mice support that CB 1R-BiP complexes act as fine-tuners of anxiety, one of the most frequent undesired effects of cannabis use. The interaction between CB 1R and BiP occurs selectively on terminals of GABAergic (inhibitory) neurons, and induces a remarkable shift in the CB 1R-associated signaling profile. Here, we found that cannabinoid CB 1 receptor (CB 1R), the primary molecular target of the bioactive constituents of cannabis, interacts specifically with an intracellular protein called BiP. SIGNIFICANCE STATEMENT Cannabis use is increasing worldwide, so innovative studies aimed to understand its complex mechanism of neurobiological action are warranted. Together, by identifying BiP as a CB 1R-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. Behavioral studies using cannabinoid-treated male BiP +/− mice supported that CB 1R-BiP complexes modulate cannabinoid-evoked anxiety, one of the most frequent undesired effects of cannabis. In situ proximity ligation assays conducted on brain samples from various genetic mouse models of conditional loss or gain of CB 1R expression allowed to map CB 1R-BiP complexes selectively on terminals of GABAergic neurons. BiP selectively shaped agonist-evoked CB 1R signaling by blocking an “alternative” G q/11 protein-dependent signaling module while leaving the “classical” G i/o protein-dependent inhibition of the cAMP pathway unaffected. We next found that CB 1R and BiP interact specifically in vitro, and mapped the interaction site within the CB 1R C-terminal (intracellular) domain and the BiP C-terminal (substrate-binding) domain-α. Here, by using a yeast two-hybrid-based high-throughput screening, we identified BiP as a potential CB 1R-interacting protein. 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 CB 1R-dependent signaling. Cannabinoids, the bioactive constituents of cannabis, exert a wide array of effects on the brain by engaging Type 1 cannabinoid receptor (CB 1R).
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