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Volume 272, Number 41, Issue of October 10, 1997 pp. 26062-26071
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

Discovery of a High Affinity Radioligand for the Human Orphan Receptor, Bombesin Receptor Subtype 3, Which Demonstrates That It Has a Unique Pharmacology Compared with Other Mammalian Bombesin Receptors

(Received for publication, March 3, 1997, and in revised form, May 30, 1997)

Samuel A. Mantey , H. Christian Weber , Eduardo Sainz ^§ , Mark Akeson ^§ , Richard R. Ryan , Tapas K. Pradhan , Robert P. Searles ^¶ , Eliot R. Spindel ^¶ , James F. Battey ^§ , David H. Coy and Robert T. Jensen

From the  Digestive Diseases Branch, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-1804, ^§ National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, the ^¶ Division of Neuroscience, Oregon Primate Research Center, Beaverton, Oregon 97006, and  Peptide Research Laboratories, Tulane University, New Orleans, Louisiana 70117

An orphan receptor discovered in 1993 was called bombesin receptor subtype 3 (BRS-3) because of 47-51% amino acid identity with bombesin (Bn) receptors. Its pharmacology is unknown, because no naturally occurring tissues have sufficient receptors to allow studies. We made two cell lines stably expressing the human BRS-3 (hBRS-3). hBRS-3 was overexpressed in the human non-small cell lung cancer cells, NCI-H1299, and the other was made in Balb 3T3 cells, which lack endogenous BRS-3. [D-Phe⁶,-Ala¹¹,Phe¹³,Nle¹⁴]Bn-(6-14) (where Nle represents norleucine) was discovered to have high potency for stimulating inositol phosphate formation in both cell lines. [¹²⁵I-D-Tyr⁶,-Ala¹¹,Phe¹³, Nle¹⁴]Bn-(6-14) bound to both cell lines with high affinity. Neither Bn nor 14 other naturally occurring Bn peptides bound to hBRS-3 with a K_d <1000 nM. Twenty-six synthetic peptides that are high affinity agonists or antagonists at other bombesin receptors had an affinity >1000 nM. Guanosine 5-(,-imido)triphosphate inhibited binding to both cells due to a change in receptor affinity. These results demonstrate hBRS-3 has a unique pharmacology. It does not interact with high affinity with any known natural agonist or high affinity antagonist of the Bn receptor family, suggesting the natural ligand is either an undiscovered member of the Bn peptide family or an unrelated peptide. The availability of these cell lines and the hBRS-3 ligand should facilitate identification of the natural ligand for BRS-3, its pharmacology, and cell biology.

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