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

Abstract

Opioid receptors are the therapeutic targets of narcotic analgesics. All three types of opioid receptors (l, d and j) are prototypical G i -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 d-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 l-opioid receptor could stimulate JNK in both SH-SY5Y cells and transfected COS-7 cells. The mechanism by which the l-opioid receptor stimulated JNK was delineated with the use of specific inhibitors and dominant-negative mutants of signaling intermediates. Activation of JNK by the l-opioid receptor was mediated through Gbc, Src kinase, son-of-sevenless (Sos), Rac and Cdc42. Interestingly, unlike the d-opioid receptors, the l-opioid receptor required phosphatidylinositol-3 kinase (PI3K) to activate JNK. The l-opioid receptor-induced JNK activation was effectively inhibited by wortmannin or the coexpression of a dominant negative mutant of PI3Kc. Like the d-opioid receptor, activation of JNK by the j-opioid receptor occurred in a PI3K-independent manner. These studies revealed that the l-opioid receptor utilize a distinct mechanism to regulate JNK.

c-Jun N-terminal Kinase Is Necessary for Platelet-derived Growth Factor-mediated Chemotaxis in Primary Fibroblasts

“…However, this pathway appears not to be involved in PDGF-BB-mediated JNK activation, since a ROCK inhibitor did not block JNK activation (data not shown). It has been reported that for some receptor systems PI 3-kinase is important for JNK activation, possibly through activation of Rac or Cdc42 (23,24). Therefore, we investigated the role of PI 3-kinase in the PDGF-BBinduced JNK activation.…”

Opioids As Modulators of Cell Death and Survival—Unraveling Mechanisms and Revealing New Indications

“…Erk activation also occurs following treatment with selective DOR and KOR agonists (Hedin et al, 1999;Kam et al, 2004;Narita et al, 2002;Persson et al, 2003). As the Erk phosphorylation cascade ranks among the main signaling pathways involved in mitogenic responses to external stimuli, it may be suggested that Erk is one messenger by which opioids transmit their neuroprotective or survival-promoting effects.…”

G Protein regulation of MAPK networks

“…However, in both Ga i -and Gbg i -mediated activation of JNK, a tyrosine kinase is involved in the activation of the respective small GTPases (Yamauchi et al, 1999(Yamauchi et al, , 2000, presumably involving tyrosine kinase responsive-specific GEFs (Shou et al, 1995;van Biesen et al, 1995;Miyamoto et al, 2003). Similar to the activation of the ERK module by Gbg i -subunit, the activation of JNK by Gbg i appears to require a PI3K activity in certain cellular contexts, such as the activation of G i -coupled m-opioid receptor (Kam et al, 2004).…”