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Morphine-Induced μ-Opioid Receptor Internalization: A Paradox Solved in Neurons

Editor's Note: These short reviews of a recent paper in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to mimic the journal clubs that exist in your own departments or institutions. For more information on the format and purpose of the Journal Club, please see Review of Haberstock-Debic et al. The G-protein-coupled receptor (GPCR) superfamily of seven transmembrane domain proteins modulates a broad array of vital physiological responses ranging from sensory perception to immunity, chemo-taxis, and neurotransmission. After stimulation , these receptors activate their respective heterotrimeric G-proteins, initiating cascades of intracellular signaling events. Subsequently, stimulation results in the phosphorylation of receptors by GPCR kinases (GRKs), leading to the recruitment of members of a family of scaffolding proteins termed arrestins. Two members of the arrestin family are specifically expressed in photoreceptors, whereas two others, ␤-arrestin-1 and ␤-arrestin-2, are expressed in all other cell types. Interaction of arrestins with GPCRs (Fig. 1 A) results in an uncoupling of G-protein signaling from receptors (receptor desensitization), a recruitment of the endocytic machinery leading to receptor internalization, and, in some cases, the formation of arrestin-dependent signal-ing complexes by which GPCRs can mediate signaling without an active participation of G-proteins (Gainetdinov et al., 2004; Beaulieu et al., 2005). GPCR regulation by arrestins and GRKs has been studied extensively in het-erologous cellular systems, mostly using human embryonic kidney 293 (HEK293) cells. Although this approach has allowed functional characterization of arrestins, GRKs, and other associated proteins, direct extrapolation of results obtained in these model systems to physiological GPCR responses in the CNS has remained problematic. For instance, stimulation of ␮-opioid receptors (MORs) by morphine in HEK293 cells does not trigger rapid receptor phosphorylation and internaliza-tion (Whistler et al., 1999). In contrast, nonrewarding opiates such as D-Ala 2-N-Me-Phe 4-Glycol 5-enkephalin (DAMGO) and methadone provoke rapid internal-ization of MORs, suggesting that the abuse potential of morphine and development of drug tolerance may come in part from a lack of receptor internalization (Whistler et al., 1999). These in vitro observations suggest that GRKs and ar-restins should play a small role in regulating the effects of morphine in the CNS. Paradoxically, mice lacking the arrestin family protein ␤-arrestin-2 (␤Arr2 knockout) display enhanced behavioral responses and G-protein-mediated sig-naling in response to morphine (Bohn et al., 1999). Moreover, these mice fail to develop tolerance to this drug (Bohn et al., 2000), indicating that ␤-arrestin-2 does indeed regulate morphine responsiveness in …