Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase
| Autor: | Shao En Ong, Selena S. Schattauer, Lauren M. Burgeno, Jamie R. Kuhar, Charles Chavkin, Paul E. M. Phillips, Kathryn L. Reichard, Benjamin B. Land, Antony D. Abraham |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Pyrrolidines Enkephalin medicine.drug_class Science Benzeneacetamides Receptors Opioid mu General Physics and Astronomy Pharmacology GTP-Binding Protein alpha Subunits Gi-Go κ-opioid receptor General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Mice 0302 clinical medicine Palmitoylation Opioid receptor Dopamine receptor D2 medicine Animals Phosphorylation lcsh:Science Receptor Multidisciplinary Morphine Chemistry Receptors Dopamine D2 Receptors Opioid kappa JNK Mitogen-Activated Protein Kinases NADPH Oxidases General Chemistry Drug Tolerance Enkephalin Ala(2)-MePhe(4)-Gly(5) 3. Good health Analgesics Opioid Fentanyl 030104 developmental biology Opioid Receptors Opioid lcsh:Q Lipid modification Reactive Oxygen Species 030217 neurology & neurosurgery medicine.drug Peroxiredoxin VI |
| Zdroj: | Nature Communications Nature Communications, Vol 8, Iss 1, Pp 1-14 (2017) |
| ISSN: | 2041-1723 |
| Popis: | Inactivation of opioid receptors limits the therapeutic efficacy of morphine-like analgesics and mediates the long duration of kappa opioid antidepressants by an uncharacterized, arrestin-independent mechanism. Here we use an iterative, discovery-based proteomic approach to show that following opioid administration, peroxiredoxin 6 (PRDX6) is recruited to the opioid receptor complex by c-Jun N-terminal kinase (JNK) phosphorylation. PRDX6 activation generates reactive oxygen species via NADPH oxidase, reducing the palmitoylation of receptor-associated Gαi in a JNK-dependent manner. Selective inhibition of PRDX6 blocks Gαi depalmitoylation, prevents the enhanced receptor G-protein association and blocks acute analgesic tolerance to morphine and kappa opioid receptor inactivation in vivo. Opioid stimulation of JNK also inactivates dopamine D2 receptors in a PRDX6-dependent manner. We show that the loss of this lipid modification distorts the receptor G-protein association, thereby preventing agonist-induced guanine nucleotide exchange. These findings establish JNK-dependent PRDX6 recruitment and oxidation-induced Gαi depalmitoylation as an additional mechanism of Gαi-G-protein-coupled receptor inactivation. Opioid receptors are important modulators of nociceptive pain. Here the authors show that opioid receptor activation recruits peroxiredoxin 6 (PRDX6) to the receptor-Gαi complex by c-Jun N-terminal kinase, resulting in Gαi depalmitoylation and enhanced receptor-Gαi association. |
| Databáze: | OpenAIRE |
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