Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase
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 opioi...
| Main Authors: | , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Nature Publishing Group
2017
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| _version_ | 1797101186664366080 |
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| author | Schattauer, SS Land, BB Reichard, KL Abraham, AD Burgeno, LM Kuhar, JR Phillips, PEM Ong, SE Chavkin, C |
| author_facet | Schattauer, SS Land, BB Reichard, KL Abraham, AD Burgeno, LM Kuhar, JR Phillips, PEM Ong, SE Chavkin, C |
| author_sort | Schattauer, SS |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T05:48:16Z |
| format | Journal article |
| id | oxford-uuid:e7f5c768-a8e9-4e04-999a-e5dfe2b18cd5 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T05:48:16Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | oxford-uuid:e7f5c768-a8e9-4e04-999a-e5dfe2b18cd52022-03-27T10:43:01ZPeroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinaseJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:e7f5c768-a8e9-4e04-999a-e5dfe2b18cd5EnglishSymplectic Elements at OxfordNature Publishing Group2017Schattauer, SSLand, BBReichard, KLAbraham, ADBurgeno, LMKuhar, JRPhillips, PEMOng, SEChavkin, CInactivation 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. |
| spellingShingle | Schattauer, SS Land, BB Reichard, KL Abraham, AD Burgeno, LM Kuhar, JR Phillips, PEM Ong, SE Chavkin, C Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase |
| title | Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase |
| title_full | Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase |
| title_fullStr | Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase |
| title_full_unstemmed | Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase |
| title_short | Peroxiredoxin 6 mediates Gαi protein-coupled receptor inactivation by cJun kinase |
| title_sort | peroxiredoxin 6 mediates gαi protein coupled receptor inactivation by cjun kinase |
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