Format

Send to

Choose Destination
Br J Pharmacol. 2008 Mar;153 Suppl 1:S379-88. Epub 2007 Dec 3.

Agonist-selective mechanisms of GPCR desensitization.

Author information

1
Department of Physiology and Pharmacology, School of Medical Sciences, University of Bristol, Bristol, UK. E.Kelly@bristol.ac.uk

Abstract

The widely accepted model of G protein-coupled receptor (GPCR) regulation describes a system where the agonist-activated receptors couple to G proteins to induce a cellular response, and are subsequently phosphorylated by a family of kinases called the G protein-coupled receptor kinases (GRKs). The GRK-phosphorylated receptor then acts as a substrate for the binding of a family of proteins called arrestins, which uncouple the receptor and G protein so desensitizing the agonist-induced response. Other kinases, principally the second messenger-dependent protein kinases, are also known to play a role in the desensitization of many GPCR responses. It is now clear that there are subtle and complex interactions between GRKs and second messenger-dependent protein kinases in the regulation of GPCR function. Functional selectivity describes the ability of agonists to stabilize different active conformations of the same GPCR. With regard to desensitization, distinct agonist-activated conformations of a GPCR could undergo different molecular mechanisms of desensitization. An example of this is the mu opioid receptor (MOPr), where the agonists morphine and [D-Ala(2),N-MePhe(4),Gly-ol(5)]enkephalin (DAMGO) induce desensitization of the MOPr by different mechanisms, largely protein kinase C (PKC)- or GRK-dependent, respectively. This can be best explained by supposing that these two agonists stabilize distinct conformations of the MOPr, which are nevertheless able to couple to the relevant G-proteins and produce similar responses, yet are sufficiently different to trigger different regulatory processes. There is evidence that other GPCRs also undergo agonist-selective desensitization, but the full therapeutic consequences of this phenomenon await further detailed study.

PMID:
18059321
PMCID:
PMC2268061
DOI:
10.1038/sj.bjp.0707604
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Wiley Icon for PubMed Central
Loading ...
Support Center