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Vol. 292, Issue 2, 638-646, February 2000

Functional and Molecular Properties of the Human Recombinant Y4 Receptor: Resistance to Agonist-Promoted Desensitization1

Thierry Voisin, Mathieu Goumain, Anne-Marie Lorinet, Jean-José Maoret and Marc Laburthe

Unité de Neuroendocrinologie et Biologie Cellulaire Digestives, Institut National de la Santé et de la Recherche Médicale U410, Faculté de Médecine Xavier Bichat, Paris, France.

After stable transfection of Chinese hamster ovary cells with the human Y4 receptor, clone 29 was isolated and studied for receptor properties. The following data were obtained: 1) one class of binding site was identified by analysis of 125I-human pancreatic polypeptide (hPP) binding to cell membranes with a Kd value of 0.26 nM and a Bmax value of 1.44 pmol/mg protein; 2) the Ki values for inhibition of 125I-hPP binding by hPP, human peptide YY (hPYY), human neuropeptide Y (hNPY), and analogs were hPP (0.7 nM) < rat PP (47 nM) < hPYY (94 nM) < h[Leu31-Pro34]NPY (124 nM) << hNPY = porcine NPY(13-36) = rat D-[Trp32]NPY (>1 µM); 3) cross-linking experiments using 125I-hPP identified a single Mr 60,000 glycosylated Y4 receptor; and 4) the natural peptides hPP, hPYY, and hNPY inhibited forskolin-stimulated cAMP production in clone 29 cells with EC50 values of 0.56 nM, 218 nM, and >1 µM, respectively. The inhibitory effect of hPP was abolished when cells were incubated with pertussis toxin, indicating a pertussis toxin-sensitive Gi protein-mediated event. 5) Exposure of cells to 10 nM hPP for 24 h resulted in the absence of modification of binding capacity (1.38 versus 1.44 pmol/mg protein in control cells) or affinity (0.31 versus 0.26 nM in control cells); there also was no modification in the potency and efficacy of hPP in inhibiting forskolin-stimulated cAMP. Immunofluorescence indicated that the Y4 receptor was not internalized within the cells after 24-h treatment with 10 nM hPP. These data support that Y4 receptors are resistant to agonist-promoted desensitization and internalization. Clone 29 cells provide a valuable tool to further characterize the pharmacological aspects of human Y4 receptor.

1 This work was supported by Association pour la Recherche sur le Cancer (Grant ARC 6404), Faculté de Médecine Xavier Bichat, Universités Paris VII and Paris XI, and Centre National de la Recherche Scientifique. We thank the IFR 02 Cellules Epithéliales for confocal microscopy facilities. M.G. is supported by a doctoral grant from the Ministère de l'Education Nationale, de la Recherche et de la Technologie.

0022-3565/00/2922-0638$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 2000 by The American Society for Pharmacology and Experimental Therapeutics


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