Reactive oxygen species (ROS) generation is stimulated by κ opioid receptor activation through phosphorylated c-Jun N-terminal kinase and inhibited by p38 mitogen-activated protein kinase (MAPK) activation.

Activation of the mitogen-activated protein kinase (MAPK) c-Jun N-terminal kinase (JNK) by the G_i/o protein-coupled κ opioid receptor (KOR), μ opioid, and D2 dopamine receptors stimulates peroxiredoxin 6 (PRDX6)-mediated production of reactive oxygen species production by KOR-inactivating antagonists norbinaltorphimine (norBNI) and JDTic blocks Gα_i protein activation, but the signaling mechanisms and consequences of JNK activation by KOR agonists remain uncharacterized. Binding of arrestins to KOR causes desensitization of G protein signaling and acts as a scaffold to initiate MAPK activation. Here, we found that the KOR agonists U50,488 and dynorphin B stimulated biphasic JNK activation with an early arrestin-independent phase, requiring the small G protein RAC family small GTPase 1 (RAC1) and protein kinase C and a later arrestin-scaffolded phase, requiring RAC1 and Ras homolog family member (RHO) kinase. JNK activation by U50,488 and dynorphin B also stimulated PRDX6-dependent duanyu1670 production but with an inverted U-shaped dose-response relationship. KOR agonist-induced duanyu1670 generation resulted from the early arrestin-independent phase of JNK activation, and this duanyu1670 response was suppressed by arrestin-dependent activation of the MAPK p38. The apparent balance between p38 MAPK and signaling has important physiological implications for understanding of dynorphin activities during the stress response. To visualize these activities, we monitored KOR agonist-mediated activation of duanyu1670 in transfected live cells by two fluorescent sensors, CellROX Green and HyPerRed. These findings establish an important aspect of opioid receptor signaling and suggest that duanyu1670 induction may be part of the physiological response to KOR activation.

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