Journal
MOLECULAR PHARMACOLOGY
Volume 91, Issue 4, Pages 416-U216Publisher
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.116.106633
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Funding
- National Institutes of Health National Institute on Drug Abuse [DA024698]
- National Institute of General Medical Sciences [GM117425]
- National Science Foundation [117776]
- National Institutes of Health National Institute of Neurologic Disorders and Stroke [T32 NS007433]
- DeVries Fellowship to Carnegie Mellon University
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1517776] Funding Source: National Science Foundation
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Functional selectivity at the mu opioid receptor ( mu R), a prototypical G-protein-coupled receptor that is a physiologically relevant target for endogenous opioid neurotransmitters and analgesics, has been a major focus for drug discovery in the recent past. Functional selectivity is a cumulative effect of the magnitudes of individual signaling pathways, e.g., the G alpha(i)-mediated and the arrestin-mediated pathways for mu R. The present work tested the hypothesis that lifetimes of agonist-induced receptor-arrestin clusters at the cell surface control the magnitude of arrestin signaling, and therefore functional selectivity, at mu R. We show that endomorphin-2 (EM2),an arrestin-biased ligand for mu R, lengthens surface lifetimes of receptor-arrestin clusters significantly compared with morphine. The lengthening of lifetimes required two specific leucines on the C-terminal tail of mu R. Mutation of these leucines to alanines decreased the magnitude of arrestin-mediated signaling by EM2 without affecting G-protein signaling, suggesting that lengthened endocytic lifetimes were required for arrestin-biased signaling by EM2. Lengthening surface lifetimes by pharmacologically slowing endocytosis was sufficient to increase arrestin-mediated signaling by both EM2 and the clinically relevant agonist morphine. Our findings show that distinct ligands can leverage specific sequence elements on mu R to regulate receptor endocytic lifetimes and the magnitude of arrestin-mediated signaling, and implicate these sequences as important determinants of functional selectivity in the opioid system.
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