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The Journal of Neuroscience, May 9, 2007, 27(19):5092-5104; doi:10.1523/JNEUROSCI.1157-07.2007

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Cellular/Molecular
ß-Arrestin2 and c-Src Regulate the Constitutive Activity and Recycling of µ Opioid Receptors in Dorsal Root Ganglion Neurons

Wendy Walwyn,¹ Christopher J. Evans,¹ and Tim G. Hales²

¹Department of Psychiatry and Biobehavioral Sciences, Hatos Center, University of California, Los Angeles, Los Angeles, California 90095, and ²Departments of Pharmacology and Physiology, and Anesthesiology and Critical Care Medicine, The George Washington University, Washington, DC 20037

Correspondence should be addressed to Tim G. Hales, Department of Pharmacology and Physiology, The George Washington University, 2300 Eye Street NW, Washington, DC 20037. Email: phmtgh{at}gwumc.edu

ß-Arrestins bind to agonist-activated G-protein-coupled receptors regulating signaling events and initiating endocytosis. In ß-arrestin2^–/– (ßarr2^–/–) mice, a complex phenotype is observed that includes altered sensitivity to morphine. However, little is known of how ß-arrestin2 affects µ receptor signaling. We investigated the coupling of µ receptors to voltage-gated Ca²⁺ channels (VGCCs) in ßarr2^+/+ and ßarr2^–/– dorsal root ganglion neurons. A lack of ß-arrestin2 reduced the maximum inhibition of VGCCs by morphine and DAMGO (D-Ala²-N-Me-Phe⁴-glycol⁵-enkephalin) without affecting agonist potency, the onset of receptor desensitization, or the functional contribution of N-type VGCCs. The reduction in inhibition was accompanied by increased naltrexone-sensitive constitutive inhibitory coupling of µ receptors to VGCCs. Agonist-independent µ receptor inhibitory coupling was insensitive to CTAP (Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂), a neutral antagonist that inhibited the inverse agonist action of naltrexone. These functional changes were accompanied by diminished constitutive recycling and increased cell-surface µ receptor expression in ßarr2^–/– compared with ßarr2^+/+ neurons. Such changes could not be explained by the classical role of ß-arrestins in agonist-induced endocytosis. The localization of the nonreceptor tyrosine kinase c-Src appeared disrupted in ßarr2^–/– neurons, and there was reduced activation of c-Src by DAMGO. Using the Src inhibitor PP2 [4-amino-5-(4-chlorophenyl)-(t-butyl)pyrazolo[3,4-D]pyrimidine], we demonstrated that defective Src signaling mimics the ßarr2^–/– cellular phenotype of reduced µ agonist efficacy, increased constitutive µ receptor activity, and reduced constitutive recycling. We propose that ß-arrestin2 is required to target c-Src to constitutively active µ receptors, resulting in their internalization, providing another dimension to the complex role of ß-arrestin2 and c-Src in G-protein-coupled receptor function.

Key words: opiate; analgesia; pain; desensitization; trafficking; internalization; tolerance; MOP receptor

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Received Jan. 24, 2007; revised March 30, 2007; accepted April 1, 2007.

Correspondence should be addressed to Tim G. Hales, Department of Pharmacology and Physiology, The George Washington University, 2300 Eye Street NW, Washington, DC 20037. Email: phmtgh{at}gwumc.edu

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