Differential effects of agonists on adenylyl cyclase superactivation mediated by the kappa opioid receptors:adenylyl cyclase superactivation is independent of agonist-induced phosphorylation,Desensitization,Internalization,and Downregulation

摘要

Prolonged activation of opioid receptors followed by agonist removal leads to adenylyl cyclase (AC)superactivation.In this study,we examined in CHO cells stably expressing the human or rat kappa opioid receptor (hkor or rkor)whether agonists had differential abilities to induce AC superactivation and whether the hkor and rkor exhibited differential AC superactivation.Pretreatment of the hkor with (trans)-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)-cyclohexyl]benzeneacetamide methanesulfonate (U50,488H)induced ac superactivation in time- and dose-dependent manner,reaching a plateau at 4 h and 0.1 muM.The extents of Ac superactivation after a 4-h pretreatment of the hkor with saturating concentrations of agonists were in the order of the full agonists u50,488H,dynorphin A(1-17),(+-)-ethylketocyclazocine,etorphine,and u69,593>the high-efficacy partial agonists nalorphine>the low-efficary partial agonists nalbuphine,morphine,and pentazocine.Interestingly,the full agonist levorphanol casused much lower AC superactivation than other full agonists and reduced the AC superactivation induced by U50,488H and dynorphin A(1-17)in a dose-dependent manner.The order of relative efficacies of agonists in causig AC superactivation mediated by the rkor was similar to that mediated by the hkor and the extents of AC superactivation were slightly lower.Because the rkor does not undergo U50,488H (1 muM)-induced phosphorylatin,desensitization,interanalization,and down-regulation in these cells,the degree of AC superactivation is independent of these processes.This is among the first reports to demonstrate that relative efficacies of agonists in causing AC superactivation generally correlated wtih those in activating G proteins and a full agonist reduced ac superactivation induced by another full agonist.