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

RESEARCH ARTICLES

Quantitative Encoding of the Effect of a Partial Agonist on Individual Opioid Receptors by Multisite Phosphorylation and Threshold Detection

Elaine K. Lau1*, Michelle Trester-Zedlitz1*, Jonathan C. Trinidad2, Sarah J. Kotowski1, Andrew N. Krutchinsky2, Alma L. Burlingame2,3, and Mark von Zastrow1,4{dagger}

1 Department of Psychiatry, University of California, San Francisco, CA 94158, USA.
2 Department of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158, USA.
3 Department of Chemistry, University of California, San Francisco, CA 94158, USA.
4 Department of Cellular and Molecular Pharmacology, University of California, San Francisco, CA 94158, USA.

* These authors contributed equally to this work.

Abstract: In comparison to endogenous ligands of seven-transmembrane receptors, which typically act as full agonists, many drugs act as partial agonists. Partial agonism is best described as a "macroscopic" property that is manifest at the level of physiological systems or cell populations; however, whether partial agonists also encode discrete regulatory information at the "microscopic" level of individual receptors is not known. Here, we addressed this question by focusing on morphine, a partial agonist drug for µ-type opioid peptide receptors (MORs), and by combining quantitative mass spectrometry with cell biological analysis to investigate the reduced efficacy of morphine, compared to that of a peptide full agonist, in promoting receptor endocytosis. We showed that these chemically distinct ligands produced a complex and qualitatively similar mixture of phosphorylated opioid receptor forms in intact cells. Quantitatively, however, the different agonists promoted disproportionate multisite phosphorylation of a specific serine and threonine motif, and we found that modification at more than one residue was essential for the efficient recruitment of the adaptor protein β-arrestin that mediated subsequent endocytosis of MORs. Thus, quantitative encoding of agonist-selective endocytosis at the level of individual opioid receptors was based on the conserved biochemical principles of multisite phosphorylation and threshold detection.

{dagger} To whom correspondence should be addressed. E-mail: mark.vonzastrow{at}ucsf.edu

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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