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Plasma membrane localization of the μ-opioid receptor controls spatiotemporal signaling
- Source :
- Science Signaling. 9
- Publication Year :
- 2016
- Publisher :
- American Association for the Advancement of Science (AAAS), 2016.
-
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 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-Ala(2),N-Me-Phe(4),Gly(5)-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.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
medicine.drug_class
media_common.quotation_subject
Receptors, Opioid, mu
Biochemistry
03 medical and health sciences
chemistry.chemical_compound
Opioid receptor
medicine
Humans
Internalization
Molecular Biology
Lipid raft
Protein kinase C
media_common
Morphine
Chemistry
Beta-Arrestins
Cell Membrane
Cell Biology
Enkephalin, Ala(2)-MePhe(4)-Gly(5)
Cell biology
Analgesics, Opioid
DAMGO
HEK293 Cells
030104 developmental biology
Signal transduction
Signal Transduction
Subjects
Details
- ISSN :
- 19379145 and 19450877
- Volume :
- 9
- Database :
- OpenAIRE
- Journal :
- Science Signaling
- Accession number :
- edsair.doi.dedup.....c3a3a89371ac04bd2870cbbfc0aa0bc2