![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
TT Chiu, LY Yung and YH Wong
Department of Biology, Hong Kong University of Science and Technology, Kowloon.
Previous studies have established that the delta-selective antagonist ICI-174,864 exhibits negative intrinsic activity at the delta-opioid receptors in NG108-15 membranes. To determine whether ICI-174,864 can function as a true inverse agonist in intact cells, its ability to stimulate cAMP accumulation was examined in a human embryonic kidney 293 cell line (293/DOR) expressing the cloned murine delta-opioid receptor. Forskolin-stimulated cAMP accumulation in the 293/DOR cells was dose-dependently suppressed by the delta-selective agonist [D-Pen2, D-Pen5]enkephalin, and such inhibition was abolished by pertussis toxin or the opiate antagonist naloxone. In contrast, ICI-174,864 significantly potentiated the forskolin response. The ICI-174,864- induced enhancement of the forskolin response exhibited dose-dependency and was antagonized by [D-Pen2,D-Pen5]enkephalin and blocked by pertussis toxin. Neither ICI-174,864 nor pertussis toxin elevated the basal level of cAMP accumulation in the absence of forskolin. Other opiate antagonists, such as naloxone and naltrindole, were ineffective in enhancing the forskolin-stimulated cAMP accumulation. Elevation of cAMP levels in response to the activation of Gs (through either ligand- bound receptor or point mutation on alpha(s)) was also potentiated by ICI-174,864. Our results indicate that ICI-174,864 behaves as an inverse agonist in human embryonic kidney 293 cells stably expressing the delta-opioid receptor. The inverse agonistic effect of ICI-174,864 seemed to require Gi proteins and was clearly manifested when adenylyl cyclase was activated.
This article has been cited by other articles:
|
|
 |
|
  P. Tryoen-Toth, F. M. Decaillot, D. Filliol, K. Befort, L. H. Lazarus, P. W. Schiller, H. Schmidhammer, and B. L. Kieffer Inverse Agonism and Neutral Antagonism at Wild-Type and Constitutively Active Mutant Delta Opioid Receptors J. Pharmacol. Exp. Ther., April 1, 2005; 313(1): 410 - 421. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Szucs, K. Boda, and A. R. Gintzler Dual Effects of DAMGO [D-Ala2,N-Me-Phe4,Gly5-ol]-Enkephalin and CTAP (D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2) on Adenylyl Cyclase Activity: Implications for {micro}-Opioid Receptor Gs Coupling J. Pharmacol. Exp. Ther., July 1, 2004; 310(1): 256 - 262. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Tao and S. B. Auerbach Opioid Receptor Subtypes Differentially Modulate Serotonin Efflux in the Rat Central Nervous System J. Pharmacol. Exp. Ther., November 1, 2002; 303(2): 549 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Christopoulos and T. Kenakin G Protein-Coupled Receptor Allosterism and Complexing Pharmacol. Rev., June 1, 2002; 54(2): 323 - 374. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. A. Zaki, D. E. Keith Jr., J. B. Thomas, F. I. Carroll, and C. J. Evans Agonist-, Antagonist-, and Inverse Agonist-Regulated Trafficking of the delta -Opioid Receptor Correlates with, but Does Not Require, G Protein Activation J. Pharmacol. Exp. Ther., September 1, 2001; 298(3): 1015 - 1020. [Abstract] [Full Text]
|
|
|
|
 |
|
 J.-G. Liu and P. L. Prather Chronic Exposure to {micro}-Opioid Agonists Produces Constitutive Activation of {micro}-Opioid Receptors in Direct Proportion to the Efficacy of the Agonist Used for Pretreatment Mol. Pharmacol., July 1, 2001; 60(1): 53 - 62. [Abstract] [Full Text]
|
|
|
|
|
|
R. Seifert, K. Wenzel-Seifert, U. Gether, and B. K. Kobilka Functional Differences between Full and Partial Agonists: Evidence for Ligand-Specific Receptor Conformations J. Pharmacol. Exp. Ther., June 1, 2001; 297(3): 1218 - 1226. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. A. J. Becker, A. Wallace, A. Garzon, P. Ingallinella, E. Bianchi, R. Cortese, F. Simonin, B. L. Kieffer, and A. Pessi Ligands for kappa -Opioid and ORL1 Receptors Identified from a Conformationally Constrained Peptide Combinatorial Library J. Biol. Chem., September 24, 1999; 274(39): 27513 - 27522. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Befort, C. Zilliox, D. Filliol, S. Yue, and B. L. Kieffer Constitutive Activation of the delta Opioid Receptor by Mutations in Transmembrane Domains III and VII J. Biol. Chem., June 25, 1999; 274(26): 18574 - 18581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. A. Simen and R. J. Miller Structural Features Determining Differential Receptor Regulation of Neuronal Ca Channels J. Neurosci., May 15, 1998; 18(10): 3689 - 3698. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-G. Liu, M. B. Ruckle, and P. L. Prather Constitutively Active {micro}-Opioid Receptors Inhibit Adenylyl Cyclase Activity in Intact Cells and Activate G-proteins Differently than the Agonist [D-Ala2,N-MePhe4,Gly-ol5]Enkephalin J. Biol. Chem., October 5, 2001; 276(41): 37779 - 37786. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
