Abstract : The aim of the present study was to identify the N‐terminal regions of human corticotropin‐releasing factor (CRF) receptor type 1 (hCRF‐R1) that are crucial for ligand binding. Mutant receptors were constructed by replacing specific residues in hCRF‐R1 with amino acids from the corresponding position in the N‐terminal region of the human vasoactive intestinal peptide receptor type 2 (hVIP‐R2). In cyclic AMP stimulation and CRF binding assays, it was established that two regions within the N‐terminal domain were crucial for the binding of CRF receptor agonists and antagonists : one region mapping to amino acids 43‐50 and a second amino acid sequence extending from position 76 to 84 of hCRF‐R1. Recently, it was found that the latter sequence plays a very important role in determining the high ligand selectivity of the Xenopus CRF‐R1 (xCRF‐R1). Replacement of amino acids 76‐84 of hCRF‐R1 with residues from the same segment of the hVIP‐R2 N terminus markedly reduced the binding affinity of CRF ligands. Mutation of Arg76 or Asn81 but not Gly83 of hCRF‐R1 to the corresponding amino acids of xCRF‐R1 or hVIP‐R2 resulted in 100‐1,000‐fold lower affinities for human/rat CRF, rat urocortin, and astressin. These data underline the importance of the N‐terminal domain of CRF‐R1 in high‐affinity ligand binding.
Journal of Neurochemistry – Wiley
Published: Jan 1, 1999
Keywords: ; ; ;
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