| Autor: |
Lau EK; Department of Psychiatry, University of California, San Francisco, CA 94158, USA., Trester-Zedlitz M, Trinidad JC, Kotowski SJ, Krutchinsky AN, Burlingame AL, von Zastrow M |
| Jazyk: |
angličtina |
| Zdroj: |
Science signaling [Sci Signal] 2011 Aug 09; Vol. 4 (185), pp. ra52. |
| DOI: |
10.1126/scisignal.2001748 |
| Abstrakt: |
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. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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