Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling

Michelle Halls, Holly R Yeatman, Cameron J Nowell, Georgina L Thompson, Arisbel Batista Gondin, Srgjan Civciristov, Nigel W Bunnett, Nevin A Lambert, Daniel P Poole, Meritxell Canals

Research output: Contribution to journalArticleResearchpeer-review

46 Citations (Scopus)

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 over-expressing MOR, morphine caused a Gβγ-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 peptide DAMGO ([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 Gβγ 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.

Original languageEnglish
Article numberra16
Pages (from-to)1-13
Number of pages13
JournalScience Signaling
Volume9
Issue number414
DOIs
Publication statusPublished - 9 Feb 2016

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