| Pharmacology and intracellular signaling mechanisms of the native human orphan receptor BRS-3 in lung cancer cells. | |
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MedLine Citation:
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PMID: 9765358 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Neither the native ligand nor the cell biology of the bombesin (Bn)-related orphan receptor subtype 3 (BRS-3) is known. In this study, we used RT-PCR to identify two human lung cancer lines that contain sufficient numbers of native hBRS-3 to allow study: NCI-N417 and NCI-H720. In both cell lines, [DPhe6,betaAla11,Phe13, Nle14]Bn(6-14) stimulates [3H]inositol phosphate. In NCI-N417 cells, binding of 125I-[DTyr6,betaAla11,Phe13,Nle14]Bn(6-14) was saturable and high-affinity. [DPhe6,betaAla11,Phe13,Nle14]Bn(6-14) stimulated phospholipase D activity and a concentration-dependent release of [3H]inositol phosphate (EC50 = 25 nM) and intracellular calcium (EC50 = 14 nM); the increases in intracellular calcium were primarily from intracellular stores. hBRS-3 activation was not coupled to changes in adenylate cyclase activity, [3H]-thymidine incorporation or cell proliferation. No naturally occurring Bn-related peptides bound or activated the hBRS-3 with high affinity. Four different bombesin receptor antagonists inhibited increases in [3H]inositol phosphate. Using cytosensor microphysiometry, we found that [DPhe6,betaAla11,Phe13, Nle14]Bn(6-14) caused concentration-dependent acidification. The results show that native hBRS-3 receptors couple to phospholipases C and D but not to adenylate cyclase and that they stimulate mobilization of intracellular calcium and increase metabolism but not growth. The discovery of human cell lines with native, functional BRS-3 receptors, of new leads for a more hBRS-3-specific antagonist and of the validity of microphysiometry as an assay has yielded important tools that can be used for the identification of a native ligand for hBRS-3 and for the characterization of BRS-3-mediated biological responses. |
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Authors:
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R R Ryan; H C Weber; S A Mantey; W Hou; M E Hilburger; T K Pradhan; D H Coy; R T Jensen |
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Publication Detail:
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Type: Journal Article |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 287 ISSN: 0022-3565 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 1998 Oct |
Date Detail:
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Created Date: 1998-11-05 Completed Date: 1998-11-05 Revised Date: 2004-11-17 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: UNITED STATES |
Other Details:
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Languages: eng Pagination: 366-80 Citation Subset: IM |
Affiliation:
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Digestive Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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3T3 Cells Animals Bombesin / metabolism Calcium / metabolism Cell Division Cyclic AMP / biosynthesis DNA / biosynthesis Humans Lung Neoplasms / metabolism* Mice Phosphatidylinositols / metabolism Receptors, Bombesin / analysis, metabolism* Reverse Transcriptase Polymerase Chain Reaction |
| Chemical | |
Reg. No./Substance:
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0/Phosphatidylinositols; 0/Receptors, Bombesin; 0/bombesin receptor subtype 3; 31362-50-2/Bombesin; 60-92-4/Cyclic AMP; 7440-70-2/Calcium; 9007-49-2/DNA |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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