Biased Coupling to β-Arrestin of Two Common Variants of the CB₂ Cannabinoid Receptor

β-arrestins are partners of the G protein-coupled receptors (GPCRs), regulating their intracellular trafficking and signaling. Development of biased GPCR agonists, selectively targeting either G protein or β-arrestin pathways, are in the focus of interest due to their therapeutic potential in different pathological conditions. The CB₂ cannabinoid receptor (CB₂R) is a GPCR involved in various functions in the periphery and the central nervous system. Two common occurring variants of CB₂R, harboring Q63R or L133I missense mutations, have been implicated in the development of a diverse set of disorders. To evaluate the effect of these mutations, we characterized the binding profile of these mutant CB₂ receptors to G proteins and β-arrestin2. Although their ability to inhibit cAMP signaling was similar, the Q63R mutant had increased, whereas the L133I mutant receptor had decreased β-arrestin2 binding. In line with these observations, the variants also had altered intracellular trafficking. Our results show that two common variants of the CB₂ receptor have biased signaling properties, which may contribute to the pathogenesis of the associated disorders and may offer CB₂R as a target for further development of biased receptor activation strategies.