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Nat Commun. 2017 Sep 29;8(1):743. doi: 10.1038/s41467-017-00791-2.

Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase.

Author information

1
Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, 98195, USA.
2
Department of Psychiatry, University of Washington School of Medicine, Seattle, WA, 98195, USA.
3
Department of Pharmacology, University of Washington School of Medicine, Seattle, WA, 98195, USA. cchavkin@u.washington.edu.

Abstract

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.

PMID:
28963507
PMCID:
PMC5622097
DOI:
10.1038/s41467-017-00791-2
[Indexed for MEDLINE]
Free PMC Article

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