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Sci. Signal., 9 August 2011
Vol. 4, Issue 185, p. ra52
[DOI: 10.1126/scisignal.2001748]


Editor's Summary

Decoding the Response to Morphine
Although the drug morphine shares with the endogenous opioid peptide enkephalin the ability to bind to and stimulate µ-type opioid receptors (MORs), morphine is much less efficient at stimulating receptor internalization by endocytosis. In addition, morphine is less effective than enkephalin (or its analog DAMGO) at stimulating receptor phosphorylation, a prerequisite for endocytosis, when assessed at the cellular level. With mass spectrometry and microscopy techniques, Lau et al. measured the differential effects of the two agonists at the level of individual receptors, which revealed differential phosphorylation of a particular serine and threonine motif within the MOR C-terminal tail. The information "encoded" by receptor phosphorylation was "decoded" by the endocytic adaptor protein β-arrestin such that β-arrestin was only efficiently recruited to MORs that had been stimulated by DAMGO. Together, these results suggest that the selective effects of agonists on receptor endocytosis are encoded by multisite phosphorylation of receptors.

Citation: E. K. Lau, M. Trester-Zedlitz, J. C. Trinidad, S. J. Kotowski, A. N. Krutchinsky, A. L. Burlingame, M. von Zastrow, Quantitative Encoding of the Effect of a Partial Agonist on Individual Opioid Receptors by Multisite Phosphorylation and Threshold Detection. Sci. Signal. 4, ra52 (2011).

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Differentiation of Opioid Drug Effects by Hierarchical Multi-Site Phosphorylation.
S. Just, S. Illing, M. Trester-Zedlitz, E. K. Lau, S. J. Kotowski, E. Miess, A. Mann, C. Doll, J. C. Trinidad, A. L. Burlingame, et al. (2013)
Mol. Pharmacol. 83, 633-639
   Abstract »    Full Text »    PDF »
Increased Agonist Affinity at the {mu}-Opioid Receptor Induced by Prolonged Agonist Exposure.
W. T. Birdsong, S. Arttamangkul, M. J. Clark, K. Cheng, K. C. Rice, J. R. Traynor, and J. T. Williams (2013)
J. Neurosci. 33, 4118-4127
   Abstract »    Full Text »    PDF »
Regulation of {micro}-Opioid Receptors: Desensitization, Phosphorylation, Internalization, and Tolerance.
J. T. Williams, S. L. Ingram, G. Henderson, C. Chavkin, M. von Zastrow, S. Schulz, T. Koch, C. J. Evans, and M. J. Christie (2013)
Pharmacol. Rev. 65, 223-254
   Abstract »    Full Text »    PDF »
Serine 363 Is Required for Nociceptin/Orphanin FQ Opioid Receptor (NOPR) Desensitization, Internalization, and Arrestin Signaling.
N. R. Zhang, W. Planer, E. R. Siuda, H.-C. Zhao, L. Stickler, S. D. Chang, M. A. Baird, Y.-Q. Cao, and M. R. Bruchas (2012)
J. Biol. Chem. 287, 42019-42030
   Abstract »    Full Text »    PDF »
Morphine Desensitization and Cellular Tolerance Are Distinguished in Rat Locus Ceruleus Neurons.
E. S. Levitt and J. T. Williams (2012)
Mol. Pharmacol. 82, 983-992
   Abstract »    Full Text »    PDF »
Endomorphin-2: A Biased Agonist at the {mu}-Opioid Receptor.
G. Rivero, J. Llorente, J. McPherson, A. Cooke, S. J. Mundell, C. A. McArdle, E. M. Rosethorne, S. J. Charlton, C. Krasel, C. P. Bailey, et al. (2012)
Mol. Pharmacol. 82, 178-188
   Abstract »    Full Text »    PDF »
GRK2 Protein-mediated Transphosphorylation Contributes to Loss of Function of {mu}-Opioid Receptors Induced by Neuropeptide FF (NPFF2) Receptors.
L. Mouledous, C. Froment, S. Dauvillier, O. Burlet-Schiltz, J.-M. Zajac, and C. Mollereau (2012)
J. Biol. Chem. 287, 12736-12749
   Abstract »    Full Text »    PDF »
Role of Receptor-attached Phosphates in Binding of Visual and Non-visual Arrestins to G Protein-coupled Receptors.
L. E. Gimenez, S. Kook, S. A. Vishnivetskiy, M. R. Ahmed, E. V. Gurevich, and V. V. Gurevich (2012)
J. Biol. Chem. 287, 9028-9040
   Abstract »    Full Text »    PDF »
Desensitization and Trafficking of {mu}-Opioid Receptors in Locus Ceruleus Neurons: Modulation by Kinases.
S. Arttamangkul, E. K. Lau, H.-W. Lu, and J. T. Williams (2012)
Mol. Pharmacol. 81, 348-355
   Abstract »    Full Text »    PDF »
Science Signaling Podcast: 9 August 2011.
M. von Zastrow and A. M. VanHook (2011)
Science Signaling 4, pc15
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