Involvement of Raf-1 in chronic δ-opioid receptor agonist-mediated adenylyl cyclase superactivation

Varga, Éva; Rubenzik, Marc; Grife, Vanessa; Sugiyama, Masano; Stropova, Dagmar; Roeske, William R.; Yamamura, Henry I.

doi:10.1016/s0014-2999(02)02220-3

Cited by 42 publications

(37 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although the exact mechanism for such signal changes is yet to be elucidated, activation of specific protein kinases and subsequent phosphorylation of AC isoforms (Avidor-Reiss et al, 1996 and other signaling molecules, such as G proteincoupled receptor kinases (GRK) 2/3 (Chakrabarti et al, 2001) have been suggested to be the key for the observed AC activation. Among all the protein kinases studied, protein kinase C (PKC), MAP kinases and Raf-1 have been implicated in the AC superactivation (Li and Chang, 1996;Varga et al, 2002;Schallmach et al, 2006). Alternative mechanisms, such as agonist-induced receptor internalization and the increase in the constitutive activities of the receptor or the switching from G i /G o -coupled to G s -coupled, also have been suggested to play a role in AC superactivation (Szucs et al, 2004;Walwyn et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

A Novel Noncanonical Signaling Pathway for theµ-Opioid Receptor

2013

View full text Add to dashboard Cite

The m-opioid receptor (OPRM1) signals as a classic G proteincoupled receptor by activating heterotrimeric G i /G o proteins resulting in adenylyl cyclase (AC) inhibition. Such AC inhibition is desensitized after prolonged agonist treatment. However, after receptor desensitization, the intracellular cAMP level remains regulated by OPRM1, as demonstrated by the intracellular cAMP level increase or AC superactivation upon removal of an agonist or addition of an antagonist. We now demonstrate that such intracellular cAMP regulation is mediated by a novel noncanonical signaling pathway resulting from OPRM1 being converted to a receptor tyrosine kinase (RTK)-like entity. This noncanonical OPRM1 signaling is initiated by the receptor recruiting and activating Src kinase within the receptor complex, leading to phosphorylation of the OPRM1 Tyr

show abstract

Section: Introductionmentioning

confidence: 99%

A Novel Noncanonical Signaling Pathway for theµ-Opioid Receptor

2013

View full text Add to dashboard Cite

show abstract

“…Since we have found earlier that a Raf-1 inhibitor, 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one (GW 5074), attenuates long-term opioid mediated AC superactivation in recombinant model cell lines (Varga et al, 2002;Yue et al, 2006), we hypothesize that Raf-1 mediated AC superactivation upon sustained opioid treatment, via activation of PKA, may contribute to sustained opioid-mediated augmentation of pain neurotransmitter release. In the present study we tested the effect of sustained morphine treatment on intracellular cAMP production and basal CGRP release in primary cultured DRG neurons.…”

Section: Introductionmentioning

confidence: 99%

Sustained morphine treatment augments basal CGRP release from cultured primary sensory neurons in a Raf-1 dependent manner

Yue

Tumati

Navratilova

et al. 2008

European Journal of Pharmacology

View full text Add to dashboard Cite

Recent studies suggest that sustained morphine-mediated paradoxical pain may play an important role in the development of analgesic tolerance. The intracellular signal transduction pathways involved in sustained opioid mediated augmentation of spinal pain neurotransmitter (such as calcitonin gene-related peptide (CGRP)) release are not fully clarified. Cyclic AMP (cAMP)-dependent protein kinase (PKA) plays an important role in the modulation of presynaptic neurotransmitter release. Moreover, we have shown earlier that sustained opioid agonist treatment leads to a Raf-1-dependent sensitization of adenylyl cyclase(s) (AC superactivation), augmenting forskolin-stimulated cAMP formation upon opioid withdrawal (cAMP overshoot). Therefore, in the present study we examined the role of Raf-1 in sustained morphine-mediated regulation of cAMP formation and basal CGRP release in vitro, in cultured neonatal rat dorsal root ganglion (DRG) neurons. We found that sustained morphine treatment significantly augments intracellular cAMP production as well as basal CGRP release from cultured neonatal rat DRG neurons. The selective PKA inhibitor, H-89, attenuates the sustained morphine-mediated augmentation of basal CGRP release, indicating that the cAMP/PKA pathway plays an important role in regulation of CGRP release from sensory neurons. Since our present data also demonstrated that selective Raf-1 inhibitor, GW 5074, attenuated both the cAMP overshoot and the augmentation of CGRP release mediated by sustained morphine in neonatal rat DRG neurons, we suggest that Raf-1-mediated sensitization of the intracellular cAMP formation may play an important role in sustained morphine-mediated augmentation of spinal pain neurotransmitter release.

show abstract

“…At the OR, chronic opioid treatment causes a compensatory increase in basal cAMP levels, referred to as Adenylyl Cyclase (AC) super activation. AC super activation may play a physiological role in developing opioid tolerance, dependence and withdrawal [5,6]. Chronic treatment with DynA led to greater AC super activation than treatment with DynB or Leu-Enk, which similarly induce AC super activation (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

“…GTPS stimulation assays were performed using CHO cells expressing the OR, analogous to previous reports [5]. -Arrestin-2 recruitment assays (DiscoveRx) were performed by manufacturer's protocol.…”

Section: Resultsmentioning

confidence: 99%