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

Michelle L. 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 journalArticle

33 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 (US)
Article numberra16
JournalScience Signaling
Volume9
Issue number414
DOIs
StatePublished - Feb 9 2016

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Opioid Receptors
Cell membranes
Cell Membrane
Extracellular Signal-Regulated MAP Kinases
Morphine
Protein Kinase C
Ligands
Heterotrimeric GTP-Binding Proteins
Phosphorylation
Guanine Nucleotides
Opioid Peptides
Enkephalins
Opioid Analgesics
Blood Proteins
Carrier Proteins
Membrane Proteins
Kidney

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Halls, M. L., Yeatman, H. R., Nowell, C. J., Thompson, G. L., Gondin, A. B., Civciristov, S., ... Canals, M. (2016). Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling. Science Signaling, 9(414), [ra16]. https://doi.org/10.1126/scisignal.aac9177

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

In: Science Signaling, Vol. 9, No. 414, ra16, 09.02.2016.

Research output: Contribution to journalArticle

Halls, ML, Yeatman, HR, Nowell, CJ, Thompson, GL, Gondin, AB, Civciristov, S, Bunnett, NW, Lambert, NA, Poole, DP & Canals, M 2016, 'Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling', Science Signaling, vol. 9, no. 414, ra16. https://doi.org/10.1126/scisignal.aac9177
Halls ML, Yeatman HR, Nowell CJ, Thompson GL, Gondin AB, Civciristov S et al. Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling. Science Signaling. 2016 Feb 9;9(414). ra16. https://doi.org/10.1126/scisignal.aac9177
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. / Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling. In: Science Signaling. 2016 ; Vol. 9, No. 414.
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