Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks.

Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks.

Publication date: Sep 12, 2019

Ligand-dependent differences in the regulation and internalization of the mu-opioid receptor (MOR) have been linked to the severity of adverse effects that limit opiate use in pain management. MOR activation by morphine or [D-Ala2,N-MePhe4,Gly-ol]-enkephalin (DAMGO) causes differences in spatiotemporal signaling dependent on MOR distribution at the plasma membrane. Morphine stimulation of MOR activates a Gai/o-Gbg-protein kinase C (PKC)a phosphorylation pathway that limits MOR distribution and is associated with a sustained increase in cytosolic extracellular signal-regulated kinase (ERK) activity. In contrast, DAMGO causes a redistribution of the MOR at the plasma membrane (before receptor internalization), that facilitates transient activation of cytosolic and nuclear ERK. Here, we used proximity biotinylation proteomics to dissect the different protein-interaction networks that underlie the spatiotemporal signaling of morphine and DAMGO. We found that DAMGO, but not morphine, activates Ras-related C3 botulinum toxin substrate 1 (Rac1). Both Rac1 and nuclear ERK activity was dependent on the scaffolding proteins IQ motif-containing GTPase-activating protein-1 (IQGAP1) and Crk-like protein (CRKL). In contrast, morphine increased the proximity of the MOR to desmosomal proteins, which form specialized and highly ordered membrane domains. Knockdown of two desmosomal proteins, junction plakoglobin (JUP) or desmocolin-1 (DSC1), switched the morphine spatiotemporal signaling profile to mimic that of DAMGO, resulting in a transient increase in nuclear ERK activity. The identification of the MOR-interaction networks that control differential spatiotemporal signaling reported here is an important step towards understanding how signal compartmentalization contributes to opioid-induced responses including anti-nociception and the development of tolerance and dependence.

Civciristov, S., Huang, C., Liu, B., Marquez, E.A., Gondin, A.B., Schittenhelm, R.B., Ellisdon, A.M., Canals, M., and Halls, M.L. Ligand-dependent spatiotemporal signaling profiles of the mu-opioid receptor are controlled by distinct protein-interaction networks. 04000. 2019 J Biol Chem.

Concepts Keywords
Botulinum Toxin Interaction networks
Cytosolic Protein interaction networks
Desmosomal Pain management
Differential Branches of biology
Enkephalin Opioids
ERK Opioid receptors
Extracellular Signal transduction
GTPase Cell biology
JUP RAC1
Kinase Morphine
Membrane G protein-coupled receptor
MOR Μ-opioid receptor
Morphine DAMGO
Motif Cell signaling
Mu Opioid Receptor Proteomics
Nociception
Opiate
Opioid
Pain Management
Phosphorylation
Plakoglobin
Plasma Membrane
Protein
Proteomics
Rac1
Ras
Receptor Internalization
Scaffolding
Substrate

Semantics

Type Source Name
disease MESH development
gene UNIPROT PTPN5
gene UNIPROT DSC1
gene UNIPROT RCAN1
gene UNIPROT JUP
gene UNIPROT CRKL
gene UNIPROT IQGAP1
gene UNIPROT RASA1
gene UNIPROT RAC1
gene UNIPROT EPHB2
gene UNIPROT CFB
drug DRUGBANK Glycine
drug DRUGBANK Morphine

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