Details

Autor(en) / Beteiligte

• Zhang, Jie
• Stephen S. G. Ferguson
• Barak, Larry S.
• Bodduluri, Sobha R.
• Laporte, Stephane A.
• Law, Ping-Yee
• Caron, Marc G.

Titel

Role for G Protein-Coupled Receptor Kinase in Agonist-Specific Regulation of μ -opioid Receptor Responsiveness

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 1998-06, Vol.95 (12), p.7157-7162

Ort / Verlag

United States: National Academy of Sciences of the United States of America

Erscheinungsjahr

1998

Quelle

MEDLINE

Beschreibungen/Notizen

• The G protein-coupled μ -opioid receptor (μ OR) mediates the physiological effects of endogenous opioid peptides as well as the structurally distinct opioid alkaloids morphine and etorphine. An intriguing feature of μ OR signaling is the differential receptor trafficking and desensitization properties following activation by distinct agonists, which have been proposed as possible mechanisms related to opioid tolerance. Here we report that the ability of distinct opioid agonists to differentially regulate μ OR internalization and desensitization is related to their ability to promote G protein-coupled receptor kinase (GRK)-dependent phosphorylation of the μ OR. Although both etorphine and morphine effectively activate the μ OR, only etorphine elicits robust μ OR phosphorylation followed by plasma membrane translocation of β -arrestin and dynamin-dependent receptor internalization. In contrast, corresponding to its inability to cause μ OR internalization, morphine is unable to either elicit μ OR phosphorylation or stimulate β -arrestin translocation. However, upon the overexpression of GRK2, morphine gains the capacity to induce μ OR phosphorylation, accompanied by the rescue of β -arrestin translocation and receptor sequestration. Moreover, overexpression of GRK2 also leads to an attenuation of morphine-mediated inhibition of adenylyl cyclase. These findings point to the existence of marked differences in the ability of different opioid agonists to promote μ OR phosphorylation by GRK. These differences may provide the molecular basis underlying the different analgesic properties of opioid agonists and contribute to the distinct ability of various opioids to induce drug tolerance.