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Vol. 296, Issue 1, 113-120, January 2001

Different Binding Modes of Amphibian and Human Corticotropin-Releasing Factor Type 1 and Type 2 Receptors: Evidence for Evolutionary Differences

Frank M. Dautzenberg, Gabrielle Py-Lang, Jacqueline Higelin, Christophe Fischer, Matthew B. Wright and Gerda Huber

F. Hoffmann-La Roche Ltd., Pharma Division, Preclinical Research, Basel, Switzerland

The binding characteristics of corticotropin-releasing factor (CRF) type 1 (CRF1) and type 2 (CRF2) receptors from human (hCRF1 and hCRF2alpha ) and Xenopus (xCRF1 and xCRF2) were compared using four different 125I-labeled CRF analogs, the agonists 125I-CRF and 125I-sauvagine, and the antagonists 125I-astressin (125I-AST) and 125I-antisauvagine-30 (125I-aSVG). The hCRF2alpha and xCRF2 receptors bound all four radioligands with different affinities, whereas hCRF1 did not bind 125I-aSVG, and xCRF1 bound neither 125I-sauvagine nor 125I-aSVG. Competitive binding studies using unlabeled agonists and antagonists with hCRF1 and hCRF2alpha receptors revealed that most agonists exhibited higher affinity in displacing agonist radioligands compared with displacement of antagonist radioligands. Exceptions were the agonists human and rat urocortin, which displayed high-affinity binding in the presence of either 125I-labeled agonist or antagonist ligands. In contrast, the affinities of antagonists were independent of the nature of the radioligand. We also found that, in contrast to the mammalian CRF receptors, the affinity of ligand binding to xCRF1 and xCRF2 receptors strongly depended on the nature of the radioligand used for competition. For xCRF1, competitors showed different rank order binding profiles with 125I-CRF compared with 125I-AST as the displaceable ligand. Similarly, binding of competitors to the xCRF2 receptor showed markedly different profiles with 125I-CRF as the competed ligand compared with the other radioligands. These data demonstrate that amphibian CRF receptors have distinctly different binding modes compared with their mammalian counterparts.

0022-3565/01/2961-0113$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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