TY - JOUR
T1 - Opioid agonists have different efficacy profiles for G protein activation, rapid desensitization, and endocytosis of Mu-opioid receptors
AU - Borgland, Stephanie L.
AU - Connor, Mark
AU - Osborne, Peregrine B.
AU - Furness, John B.
AU - Christie, MacDonald J.
PY - 2003/5/23
Y1 - 2003/5/23
N2 - The differential ability of various μ-opioid receptor (MOP) agonists to induce rapid receptor desensitization and endocytosis of MOP could arise simply from differences in their efficacy to activate G proteins or, alternatively, be due to differential capacity for activation of other signaling processes. We used AtT20 cells stably expressing a low density of FLAG-tagged MOP to compare the efficacies of a range of agonists to 1) activate G proteins using inhibition of calcium channel currents (ICa) as a reporter before and after inactivation of a fraction of receptors by β-chlornaltrexamine, 2) produce rapid, homologous desensitization of ICa inhibition, and 3) internalize receptors. Relative efficacies determined for G protein coupling were [Tyr-D-Ala-Gly-MePhe-Glyol]enkephalin (DAMGO) (1) ≥ methadone (0.98) > morphine (0.58) > pentazocine (0.15). The same rank order of efficacies for rapid desensitization of MOP was observed, but greater concentrations of agonist were required than for G protein activation. By contrast, relative efficacies for promoting endocytosis of MOP were DAMGO (1) > methadone (0.59) ≫ morphine (0.07) ≥ pentazocine (0.03). These results indicate that the efficacy of opioids to produce activation of G proteins and rapid desensitization is distinct from their capacity to internalize μ-opioid receptors but that, contrary to some previous reports, morphine can produce rapid, homologous desensitization of MOP.
AB - The differential ability of various μ-opioid receptor (MOP) agonists to induce rapid receptor desensitization and endocytosis of MOP could arise simply from differences in their efficacy to activate G proteins or, alternatively, be due to differential capacity for activation of other signaling processes. We used AtT20 cells stably expressing a low density of FLAG-tagged MOP to compare the efficacies of a range of agonists to 1) activate G proteins using inhibition of calcium channel currents (ICa) as a reporter before and after inactivation of a fraction of receptors by β-chlornaltrexamine, 2) produce rapid, homologous desensitization of ICa inhibition, and 3) internalize receptors. Relative efficacies determined for G protein coupling were [Tyr-D-Ala-Gly-MePhe-Glyol]enkephalin (DAMGO) (1) ≥ methadone (0.98) > morphine (0.58) > pentazocine (0.15). The same rank order of efficacies for rapid desensitization of MOP was observed, but greater concentrations of agonist were required than for G protein activation. By contrast, relative efficacies for promoting endocytosis of MOP were DAMGO (1) > methadone (0.59) ≫ morphine (0.07) ≥ pentazocine (0.03). These results indicate that the efficacy of opioids to produce activation of G proteins and rapid desensitization is distinct from their capacity to internalize μ-opioid receptors but that, contrary to some previous reports, morphine can produce rapid, homologous desensitization of MOP.
UR - http://www.scopus.com/inward/record.url?scp=0037805628&partnerID=8YFLogxK
U2 - 10.1074/jbc.M300525200
DO - 10.1074/jbc.M300525200
M3 - Article
C2 - 12642578
AN - SCOPUS:0037805628
SN - 0021-9258
VL - 278
SP - 18776
EP - 18784
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 21
ER -