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Melief, Erica J.; Miyatake, Mayumi; Bruchas, Michael R.; Chavkin, Charles; Amara, Susan G.
Proceedings of the National Academy of Sciences - PNAS, 06/2010, Letnik: 107, Številka: 25Journal Article
Ligand-directed signaling has been suggested as a basis for the differences in responses evoked by otherwise receptor-selective agonists. The underlying mechanisms are not understood, yet clearer definition of this concept may be helpful in the development of novel, pathway-selective therapeutic agents. We previously showed that κ-opioid receptor activation of JNK by one class of ligand, but not another, caused persistent receptor inactivation. In the current study, we found that the μ-opioid receptor (MOR) could be similarly inactivated by a specific ligand class including the prototypical opioid, morphine. Acute analgesic tolerance to morphine and related opioids (morphine-6-glucuronide and buprenorphine) was blocked by JNK inhibition, but not by G protein receptor kinase 3 knockout. In contrast, a second class of μ-opioids including fentanyl, methadone, and oxycodone produced acute analgesic tolerance that was blocked by G protein receptor kinase 3 knockout, but not by JNK inhibition. Acute MOR desensitization, demonstrated by reduced D-Ala²-Met⁵-Glyol-enkephalin—stimulated ³⁵SGTPγS binding to spinal cord membranes from morphine-pretreated mice, was also blocked by JNK inhibition; however, desensitization of D-Ala²-Met⁵-Glyol-enkephalin—stimulated ³⁵SGTPγS binding following fentanyl pretreatment was not blocked by JNK inhibition. JNK-mediated receptor inactivation of the κ-opioid receptor was evident in both agonist-stimulated ³⁵SGTPγS binding and opioid analgesic assays; however, gene knockout of JNK 1 selectively blocked κ-receptor inactivation, whereas deletion of JNK 2 selectively blocked MOR inactivation. These findings suggest that ligand-directed activation of JNK kinases may generally provides an alternate mode of G protein—coupled receptor regulation.
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