Research ArticlePharmacology

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

Sci. Signal.  09 Aug 2011:
Vol. 4, Issue 185, pp. ra52
DOI: 10.1126/scisignal.2001748

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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.

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