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Research ArticleCELLULAR AND MOLECULAR

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
Journal of Pharmacology and Experimental Therapeutics January 2001, 296 (1) 113-120;
Frank M. Dautzenberg
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Gabrielle Py-Lang
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Jacqueline Higelin
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Christophe Fischer
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Matthew B. Wright
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Gerda Huber
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Abstract

The binding characteristics of corticotropin-releasing factor (CRF) type 1 (CRF1) and type 2 (CRF2) receptors from human (hCRF1 and hCRF2α) andXenopus (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) and125I-antisauvagine-30 (125I-aSVG). The hCRF2α and xCRF2 receptors bound all four radioligands with different affinities, whereas hCRF1 did not bind 125I-aSVG, and xCRF1 bound neither125I-sauvagine nor 125I-aSVG. Competitive binding studies using unlabeled agonists and antagonists with hCRF1 and hCRF2α 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 with125I-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.

Footnotes

  • Send reprint requests to: Dr. Frank M. Dautzenberg, Pharma Division, Preclinical Research, Bldg. 70-307, F-Hoffmann-La Roche LTD, CH-4070 Basel, Switzerland. E-mail:frank.dautzenberg{at}roche.com

  • This work was supported by the F. Hoffmann-La Roche AG.

  • Abbreviations:
    CRF
    corticotropin-releasing factor
    UCN
    urocortin
    GPCR
    G protein-coupled receptor
    CRF1
    CRF type 1 receptor
    CRF2
    CRF type 2 receptor
    h
    human
    x
    Xenopus
    r
    rat
    o
    ovine
    aSVG
    antisauvagine-30
    α-hel CRF
    α-helical CRF(9-41)
    AST
    astressin
    EC
    extracellular domain
    • Received June 14, 2000.
    • Accepted September 7, 2000.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 296 (1)
Journal of Pharmacology and Experimental Therapeutics
Vol. 296, Issue 1
1 Jan 2001
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Research ArticleCELLULAR AND MOLECULAR

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
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 113-120;

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Research ArticleCELLULAR AND MOLECULAR

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
Journal of Pharmacology and Experimental Therapeutics January 1, 2001, 296 (1) 113-120;
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