Type I cannabinoid receptor trafficking: all roads lead to lysosome

The majority of G-protein-coupled receptors (GPCRs) function at the cell surface, where they are activated by their ligands present in the extracellular milieu. Interestingly, type I cannabinoid receptor (CB(1) R), one of the most abundant GPCRs in the central nervous system, is predominantly intracellular. The important physiological roles of CB(1) R have sparked interest in the elucidation of the molecular mechanisms underlying the trafficking of this receptor and the role of intracellular CB(1) Rs. Thus far, results from different groups have been, at least in part, contradictory and the basis of CB(1) R intracellular localization remains controversial. In this commentary, by comparing the studies examining CB(1) R trafficking and localization, we identify technical or experimental ground responsible for the conflicting results. Finally, we propose a possible mechanism of CB(1) R trafficking that may reconcile the different models.