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- Title
Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling.
- Authors
Halls, Michelle L.; Yeatman, Holly R.; Nowell, Cameron J.; Thompson, Georgina L.; Gondin, Arisbel Batista; Civciristov, Srgjan; Bunnett, Nigel W.; Lambert, Nevin A.; Poole, Daniel P.; Canals, Meritxell
- Abstract
Differential regulation of the μ-opioid receptor (MOR), a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, contributes to the clinically limiting effects of opioid analgesics, such as morphine. We used biophysical approaches to quantify spatiotemporal MOR signaling in response to different ligands. In human embryonic kidney (HEK) 293 cells overexpressing MOR, morphine caused a Gbg-dependent increase in plasma membrane-localized protein kinase C (PKC) activity, which resulted in a restricted distribution of MOR within the plasma membrane and induced sustained cytosolic extracellular signal-regulated kinase (ERK) signaling. In contrast, the synthetic opioid peptideDAMGO ([D-Ala²,N-Me-Phe4, Gly5-ol]-enkephalin) enabled receptor redistribution within the plasma membrane, resulting in transient increases in cytosolic and nuclear ERK activity, and, subsequently, receptor internalization. When Gβγg subunits or PKCα activity was inhibited or when the carboxyl-terminal phosphorylation sites of MOR were mutated, morphine-activated MOR was released from its restricted plasma membrane localization and stimulated a transient increase in cytosolic and nuclear ERK activity in the absence of receptor internalization. Thus, these data suggest that the ligand-induced redistribution of MOR within the plasma membrane, and not its internalization, controls its spatiotemporal signaling.
- Subjects
SPATIOTEMPORAL processes; CELL membranes; OPIOID receptors; G protein coupled receptors; MORPHINE; CELLULAR signal transduction
- Publication
Science Signaling, 2016, Vol 9, Issue 414, p1
- ISSN
1945-0877
- Publication type
Article
- DOI
10.1126/scisignal.aac9177