The CB1 cannabinoid receptors are among the most highly expressed G protein coupled receptors (GPCRs) in the brain. Their activation has been associated with a wide range of behaviors, including cognition, pain perception, drug addiction, and memory consolidation, and they have been pharmaceutically targeted for pain therapies, smoking cessation, and appetite control. The CB1 receptor has been challenging to study at the molecular level given the hydrophobic nature of its lipid-based agonists and difficulties expressing the recombinant cDNA in cellular cultures. Early transfection studies in cell cultures revealed predominantly intracellular localization of the CB1 receptor and it was not clear whether this was the "normal" distribution or whether this was some artifact of the cellular model systems. However, studies of the endogenously expressed CB1 receptors using specific antibodies have shown that the there is usually a distinct intracellular, vesicular localization of the CB1 receptor. Confocal microscopy analysis reveals that the intracellular CB1 receptors are localized to vesicles, which implies that the receptors are "trafficking" or undergoing a continuous cycle of internalization and membrane relocalization. The article by McDonald et al. (p. 976) in this issue of Molecular Pharmacology addresses whether this constitutive trafficking is related to the activation state of the receptor and whether it plays a role in axonal versus somatodendritic receptor localization.
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