Phosphatidylinositol‐3 kinase is distinctively required for µ‐, but not κ‐opioid receptor‐induced activation of c‐Jun N‐terminal kinase

• Published in: Journal of neurochemistry Vol. 89; no. 2; pp. 391 - 402
• Main Authors: Kam, Angel Y. F., Chan, Anthony S. L., Wong, Yung H.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-04-2004; Blackwell
• Subjects: Animals; Biological and medical sciences; cdc42 GTP-Binding Protein - metabolism; Cell physiology; Cell receptors; Cell structures and functions; Cercopithecus aethiops; COS Cells; Enzyme Activation - physiology; Enzyme Inhibitors - pharmacology; Fundamental and applied biological sciences. Psychology; Genes, Dominant; GTP-Binding Proteins - drug effects; GTP-Binding Proteins - metabolism; Humans; JNK; JNK Mitogen-Activated Protein Kinases; Mice; Mitogen-Activated Protein Kinases - metabolism; Molecular and cellular biology; Neuropeptide receptors; Pertussis Toxin - pharmacology; Phosphatidylinositol 3-Kinases - metabolism; PI3K; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; rac GTP-Binding Proteins - metabolism; Rats; Receptors, Opioid, kappa - genetics; Receptors, Opioid, kappa - metabolism; Receptors, Opioid, mu - genetics; Receptors, Opioid, mu - metabolism; Signal transduction; small GTPases; Son of Sevenless Proteins - metabolism; Son‐of‐sevenless (Sos); Src; src-Family Kinases - metabolism; Transfection; µ‐opioid receptor; p-opioid receptor; Enzyme; Triphosphoric monoester hydrolases; Stress-activated kinase; Src; JNK; μ Opioid receptor; small GTPases; Mitogen-activated protein kinase; dGTPase; κ Opioid receptor; Esterases; δ Opioid receptor; terminal kinase; Son-of-sevenless (Sos); Signal transduction; Cell line; PI3K; c-Jun NH; Hydrolases; Phosphatidylinositol 3-kinase
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2004.02338.x

Opioid receptors are the therapeutic targets of narcotic analgesics. All three types of opioid receptors (µ, δ and κ) are prototypical Gi‐coupled receptors with common signaling characteristics in their regulation of intracellular events. Nevertheless, numerous signaling processes are differentially regulated by the three receptors. We have recently demonstrated that stimulation of δ‐opioid receptor can up‐regulate the activity of the c‐Jun N‐terminal kinase (JNK) in a pertussis toxin‐sensitive manner (Kam et al. 2003; J. Neurochem. 84, 503–513). The present study revealed that the µ‐opioid receptor could stimulate JNK in both SH‐SY5Y cells and transfected COS‐7 cells. The mechanism by which the µ‐opioid receptor stimulated JNK was delineated with the use of specific inhibitors and dominant‐negative mutants of signaling intermediates. Activation of JNK by the µ‐opioid receptor was mediated through Gβγ, Src kinase, son‐of‐sevenless (Sos), Rac and Cdc42. Interestingly, unlike the δ‐opioid receptors, the µ‐opioid receptor required phosphatidylinositol‐3 kinase (PI3K) to activate JNK. The µ‐opioid receptor‐induced JNK activation was effectively inhibited by wortmannin or the coexpression of a dominant negative mutant of PI3Kγ. Like the δ‐opioid receptor, activation of JNK by the κ‐opioid receptor occurred in a PI3K‐independent manner. These studies revealed that the µ‐opioid receptor utilize a distinct mechanism to regulate JNK.