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

Selena S. Schattauer, Benjamin B. Land, Kathryn L. Reichard, Antony D. Abraham, Lauren M. Burgeno, Jamie R. Kuhar, Paul E. M. Phillips, Shao En Ong and Charles Chavkin ()
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Selena S. Schattauer: University of Washington School of Medicine
Benjamin B. Land: University of Washington School of Medicine
Kathryn L. Reichard: University of Washington School of Medicine
Antony D. Abraham: University of Washington School of Medicine
Lauren M. Burgeno: University of Washington School of Medicine
Jamie R. Kuhar: University of Washington School of Medicine
Paul E. M. Phillips: University of Washington School of Medicine
Shao En Ong: University of Washington School of Medicine
Charles Chavkin: University of Washington School of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00791-2

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