The ligand-selective domains of corticotropin-releasing factor type 1 and type 2 receptor reside in different extracellular domains: Generation of chimeric receptors with a novel ligand-selective profile

Citation
Fm. Dautzenberg et al., The ligand-selective domains of corticotropin-releasing factor type 1 and type 2 receptor reside in different extracellular domains: Generation of chimeric receptors with a novel ligand-selective profile, J NEUROCHEM, 73(2), 1999, pp. 821-829
Citations number
37
Categorie Soggetti
Neurosciences & Behavoir
Journal title
JOURNAL OF NEUROCHEMISTRY
ISSN journal
00223042 → ACNP
Volume
73
Issue
2
Year of publication
1999
Pages
821 - 829
Database
ISI
SICI code
0022-3042(199908)73:2<821:TLDOCF>2.0.ZU;2-4
Abstract
The nonselective human corticotropin-releasing factor (hCRF) receptor 1 (hC RFR1) and the ligand-selective Xenopus CRFR1 (xCRFR1), xCRFR2, and hCRFR2 a lpha were compared. To understand the interactions of hCRF, ovine CRF (oCRF ), rat urocortin (rUcn), and sauvagine, ligands with different affinities f or type 1 and type 2 CRFRs, chimeric and mutant receptors of hCRFR1, xCRFR1 , hCRFR2 alpha, and xCRFR2 were constructed. In cyclic AMP stimulation and CRF-binding assays, it was established that different extracellular regions of CRFR1 and CRFR2 conferred their ligand selectivities. The ligand select ivity of xCRFR1 resided in five N-terminal amino acids, whereas the N-termi nus of both CRFR2 proteins did not contribute to their ligand selectivities . Chimeric receptors in which the first extracellular domain of hCRFR1 repl aced that of hCRFR2 alpha or xCRFR2 showed a similar pharmacological profil e to the two parental CRFR2 molecules. Chimeric receptors carrying the N-te rminal domain of xCRFR1 linked to hCRFR2 alpha or xCRFR2 displayed a novel pharmacological profile. hCRF, rUcn, and sauvagine were bound with high aff inity, whereas oCRF was bound with low affinity. Furthermore, when three or five residues of xCRFR1 (Gln(76), Gly(81), Val(83), His(88), Leu(89); or G ln(76), Gly(81), Val(83)) were introduced into receptor chimeras carrying t he N-terminus of hCRFR1 linked to xCRFR2, the same novel pharmacology was o bserved. These data indicate a compensation mechanism of two differentially selecting regions located in different domains of both xCRFR1 and CRFR2.