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Pharmacology and Cell Biology of the Bombesin Receptor Subtype 4 (BB4-R)

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Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, Laboratory of Molecular Biology, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland 20850, Division of Neuroscience, Oregon Primate Research Center, Beaverton, Oregon 97006, and Peptide Research Laboratories, Tulane University, New Orleans, Louisiana 70112
Cite this: Biochemistry 1999, 38, 22, 7307–7320
Publication Date (Web):May 8, 1999
Copyright © 1999 American Chemical Society

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    Recently, a fourth member of the bombesin (Bn) receptor family (fBB4-R) was isolated from a cDNA library from the brain of the frog, Bombina orientalis. Its pharmacology and cell biology are largely unknown, and no known natural cell lines or tissues possess sufficient numbers of fBB4-R's to allow either of these to be determined. To address these issues, we have used three different strategies. fBB4-R expression in cells widely used for other Bn receptor subtypes was unsuccessful as was expression in two frog cell lines. However, stable fBB4-R cell lines were obtained in CHO-K1 cells which were shown to faithfully demonstrate the correct pharmacology of the related Bn receptor, the GRP receptor, when expressed in these cells. [DPhe6,βAla11,Phe13,Nle14]Bn(6−14) was found to have high affinity (Ki = 0.4 nM) for the fBB4 receptor and 125I-[DTyr6,βala11,Phe13,Nle14]Bn(6−14) to be an excellent ligand for this receptor. The fBB4-R had a unique pharmacology for naturally occurring Bn-related agonists, with the presence of a penultimate phenylalanine being critical for high-affinity interaction. It also had a unique profile for six classes of Bn antagonists. The fBB4-R was coupled to phospholipase C with activation increasing [3H]inositol phosphates and mobilizing Ca2+ almost entirely from cellular sources. There was a close correlation between agonist the receptor occupation and the receptor activation. Three of the five classes of Bn receptor antagonists that interacted with higher affinity with the fBB4-R functioned as fBB4-R antagonists and two as partial agonists. fBB4-R activation stimulated increases in phospholipase D (PLD) over the same range of concentrations at which it activated phospholipase C. These results demonstrate that the fBB4 receptor has a unique pharmacology for agonists and antagonists and is coupled to phospholipase C and D. The availability of these cell lines, this novel ligand, and the identification of three classes of antagonists that can be used as lead compounds should facilitate the further investigation of the pharmacology and cell biology of the BB4 receptor.

     This work was partially supported by NIH grant NS35580 (E.R.S.).

     National Institutes of Health, Bethesda, Maryland.


     National Institutes of Health, Rockville, Maryland.

     Oregon Primate Research Center.

     Tulane University.


     Correspondence and Reprints to:  NIH/NIDDK/DDB, Bldg. 10, Rm. 9C-103, 10 CENTER DR MSC 1804, BETHESDA MD 20892-1804. Tel:  301/496-4201. Fax:  301/402-0600. E-mail:  robertj@bdg10.

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