The full-length complementary DNA (cDNA) of monkey corticotropin-releasing factor type 1 (CRF1) receptor was isolated from a rhesus monkey (Macaca mulatta) amygdala cDNA library. The cloned monkey CRF1 receptor cDNA has 2,374 bp with an open reading frame encoding a 415-amino acid protein. The sequence of the monkey CRF1 receptor cDNA showed a high degree of sequence identity with other species of CRF1 receptors, and being 99.5% identical to human CRF1 receptors. When monkey CRF1 was expressed into COS-7 cells, high specific binding of [125I]-ovine CRF was observed. CRF and CRF-related peptides inhibited [125I]-ovine CRF binding in a concentration-dependent manner. IC50 values of ovine CRF, human/rat CRF, sauvagine and urotensin I were 23.5 +/- 7.4, 22.7 +/- 10.8, 27.5 +/- 12.3 and 14.2 +/- 7.0 nM, respectively. CRF1 receptor specific antagonists, such as CP-154,526, SC241 and CRA1000, also inhibited the [125I]-ovine CRF binding, with IC50 values of 3.9 +/- 0.4, 43.5 +/- 8.0 and 19.8 +/- 2.0 nM, respectively. GTP and its nonhydrolyzed analogue, GTPgammaS, reduced [125I]-ovine CRF binding, while ATP had a negligible effect, thereby indicating that the monkey CRF1 receptor belongs to a family of G-protein coupled receptors. CRF and its related peptides increased cyclic AMP formation concentration-dependently in COS-7 cells transiently expressing the monkey CRF1 receptor. Monkey CRF1 was expressed abundantly in the pituitary, cerebral cortex, hippocampus, amygdala and cerebellum. Thus the monkey CRF1 receptor and the human CRF1 receptor have similar molecular and pharmacological characteristics.

01 Mar 1998·Journal of Neuroscience MethodsQ4 · MEDICINE

Pharmacological characterisation of the recombinant human CRF binding protein using a simple assay

Q4 · MEDICINE

Article

Author: Stephane Henriot ; Juergen Gottowik ; Gavin J Kilpatrick ; Roger G Clerc ; Ali Ardati

We present the pharmacological characterisation of the recombinant human corticotropin releasing factor binding protein (hCRF-BP) using a simple assay. In this assay we employed [3H]urocortin as the radioligand and, as a means to separate bound and free ligand, adsorption to activated charcoal. Using this method, approximately 60-70% of total binding was specific. Kinetic analysis revealed that association of specific [3H]urocortin binding was monophasic and slow and that the binding was irreversible. Saturation analysis showed a single saturable site of relatively high density (94 fmol per 10 microl of medium from cells transfected with the recombinant CRF binding protein). The apparent Kd for [3H]urocortin binding of 0.25 nM is similar to previously reported affinities of rat urocortin for hCRF-BP. A range of CRF-related peptides potently competed for specific [3H]urocortin binding. The rank order of potency of these agents was human/rat CRF = urotensin 1 > human urocortin > CRF6-33 > sauvagine > ovine CRF. The non-peptide CRF1 receptor antagonists CP 154,526 (N-butyl-N-[2,5-dimethyl-7-(2,4,6-trimethylphenyl)-7H-pyrrolo[2,3-d]p yri midin-4-yl]-N-ethylamine) and SC 241 ([3-(2-bromo-4-isopropyl-phenyl)-5-methyl-3H-[1,2,3]triazo lo[4,5-d]pyrimidin-7-yl]-bis-(2-methoxy-ethyl)-amine) were not active at the highest concentration tested (10(-6) M). We conclude that this is a simple and accurate assay for characterisation of the pharmacology of the recombinant CRF-BP. This assay should assist with further study of the pharmacology and function of the CRF-BP.

01 Oct 1997·NeuropharmacologyQ2 · MEDICINE

Labelling of CRF1 and CRF2 receptors using the novel radioligand, [3H]-urocortin

Q2 · MEDICINE

Article

Author: Clerc, R. G. ; Goetschy, V. ; Monsma, F. J. ; Gottowik, J. ; Henriot, S. ; Fluhman, B. ; Moreau, J.-L. ; Kitas, E. ; Kilpatrick, G. J.

The binding of the novel radioligand, [3H]-rat urocortin to homogenates of rat cerebellum and homogenates of cells stably transfected with the human CRF1, rat CRF2alpha and rat CRF2beta receptors was examined. In each case, specific reversible high affinity binding was observed (K[d]s between 0.18 and 0.31 nM). The density of sites was relatively low in the cerebellum (9 fmol/mg tissue) but high in the recombinant systems with expression levels of between 1.4 and 6.3 pmol/mg protein. Agents known to interact with CRF receptors potently competed for binding in each case. The pharmacological profile of binding to the recombinant receptors were consistent with data previously published using other radioligands. Thus, for the recombinant CRF1 receptor, binding was inhibited with similar affinity by Urocortin, sauvagine, Urotensin 1 and CRF. The non-peptidic CRF antagonists (e.g. CP 154,526 and SC 241) also potently inhibited binding. The CRF2alpha and CRF2beta receptor recombinant systems had a very similar pharmacological profile with a clear rank order of potency for the peptide ligands (Urocortin > Sauvagine > Urotensin 1 > CRF), whereas the non-peptide CRF receptor antagonists had no measurable affinity. The pharmacological profile of specific [3H]-urocortin binding to homogentates of rat cerebellum was consistent with specific labelling of a CRF1 receptor. We conclude that [3H]-urocortin is a useful tool for the study of CRF receptors with the advantages that a filtration assay can be used, all CRF receptors can be labelled with the same ligand and the benefits associated with the low energy emittor, 3H.

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