RT Journal Article
SR Electronic
T1 Allosteric Ligands for the Corticotropin Releasing Factor Type 1 Receptor Modulate Conformational States Involved in Receptor Activation
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP 1371
OP 1380
DO 10.1124/mol.107.042978
VO 73
IS 5
A1 Sam R. J. Hoare
A1 Beth A. Fleck
A1 Raymond S. Gross
A1 Paul D. Crowe
A1 John P. Williams
A1 Dimitri E. Grigoriadis
YR 2008
UL http://molpharm.aspetjournals.org/content/73/5/1371.abstract
AB Allosteric modulators of G-protein-coupled receptors can regulate conformational states involved in receptor activation ( Mol Pharmacol58:1412-1423, 2000 ). This hypothesis was investigated for the corticotropin-releasing factor type 1 (CRF1) receptor using a novel series of ligands with varying allosteric effect on CRF binding (inhibition to enhancement). For the G-protein-uncoupled receptor, allosteric modulation of CRF binding was correlated with nonpeptide ligand signaling activity; inverse agonists inhibited and agonists enhanced CRF binding. These data were quantitatively consistent with a two-state equilibrium underlying the modulation of CRF binding to the G-protein-uncoupled receptor. We next investigated the allosteric effect on CRF-stimulated G-protein coupling. Ligands inhibited CRF-stimulated cAMP accumulation regardless of their effect on the G-protein-uncoupled state. The modulators reduced CRF Emax values, suggesting that they reduced the efficacy of a CRF-bound active state to couple to G-protein. Consistent with this hypothesis, the modulators inhibited binding to a guanine nucleotide-sensitive state. Together, the results are quantitatively consistent with a model in which 1) the receptor exists in three predominant states: an inactive state, a weakly active state, and a CRF-bound fully active state; 2) allosteric inverse agonists stabilize the inactive state, and allosteric agonists stabilize the weakly active state; and 3) antagonism of CRF signaling results from destabilization of the fully active state. These findings imply that nonpeptide ligands differentially modulate conformational states involved in CRF1 receptor activation and suggest that different conformational states can be targeted in designing nonpeptide ligands to inhibit CRF signaling.