Functional differences between full and partial agonists: Evidence for ligand-specific receptor conformations

Citation
R. Seifert et al., Functional differences between full and partial agonists: Evidence for ligand-specific receptor conformations, J PHARM EXP, 297(3), 2001, pp. 1218-1226
Citations number
48
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Pharmacology & Toxicology
Journal title
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
ISSN journal
0022-3565 → ACNP
Volume
297
Issue
3
Year of publication
2001
Pages
1218 - 1226
Database
ISI
SICI code
0022-3565(200106)297:3<1218:FDBFAP>2.0.ZU;2-X
Abstract
The interaction of an agonist-bound G-protein-coupled receptor (GPCR) with its cognate G-protein initiates a sequence of experimentally quantifiable c hanges in both the GPCR and G-protein. These include the release of GDP fro m G(alpha), the formation of a ternary complex between the nucleotide-free G-protein and the GPCR, which has a high affinity for agonist, followed by the binding of GTP to G(alpha), the dissociation of the GPCR/G-protein comp lex, and the hydrolysis of GTP, The efficacy of an agonist is a measure of its ability to activate this cascade. It has been proposed that efficacy re flects the ability of the agonist to stabilize the active state of the GPCR , We examined a series of beta (2)-adrenoceptor (beta (2)AR) agonists (weak partial agonists to full agonists) for their efficacy at promoting two dif ferent steps of the G-protein activation/deactivation cycle: stabilizing th e ternary complex (high-affinity, GTP-sensitive agonist binding), and stead y-state GTPase activity. We obtained results for the wild-type beta (2)AR a nd a constitutively active mutant of the beta (2)AR (beta (2)AR(CAM)) using fusion proteins between the GPCRs and G(s alpha) to facilitate GPCR/G-prot ein interactions. There was no correlation between efficacy of ligands in a ctivating GTPase and their ability to stabilize the ternary complex at beta (2)AR(CAM). Our results suggest that the GPCR state that optimally promote s the GDP release and GTP binding is different from the GPCR state that sta bilizes the ternary complex. By strongly stabilizing the ternary complex, c ertain partial agonists may reduce the rate of G-protein turnover relative to a full agonist.