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Jak2 and Ca2+/calmodulin are key intermediates for bradykinin B-2 receptor-mediated activation of Na+/H+ exchange in KNRK and CHO cells

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Author

Summary, in English

Na+/H+ exchangers are ubiquitous in mammalian cells, carrying out key functions, such as cell volume defense, acid-base homeostasis, and regulation of the cytoskeleton. We used two screening technologies (FLIPR and microphysiometry) to characterize the signal transduction pathway used by the bradykinin beta(2) receptor to activate Na+/H+ exchange in two cell lines, KNRK and CHO. In both cell types, beta(2) receptor activation resulted in rapid increases in the rate of proton extrusion that were sodium-dependent and could be blocked by the Na+/H+ exchange inhibitors EIPA and MIA or by replacing extracellular sodium with TMA. Activation of Na+/H+ exchange by bradykinin was concentration-dependent and could be blocked by the selective beta(2) receptor antagonist HOE140, but not by the beta(1) receptor antagonist des-Arg(10)-HOE140. Inhibitors of Jak2 tyrosine kinase (genistein and AG490) and of CAM (W-7 and calmidazolium) attenuated bradykinin-induced activation of Na+/H+ exchange. Bradykinin induced formation of a complex between CAM and Jak2, supporting a regulatory role for Jak2 and CAM in the activation of Na+/H+ exchange in KNRK and CHO cells. We propose that this pathway (beta(2) receptor --> Jak2 --> CAM --> Na+/H+ exchanger) is a fundamental regulator of Na+/H+ exchange activity.

Department/s

  • Drug Target Discovery

Publishing year

2003

Language

English

Pages

281-289

Publication/Series

Assay and Drug Development Technologies

Volume

1

Issue

2

Document type

Journal article

Publisher

Mary Ann Liebert, Inc.

Topic

  • Pharmacology and Toxicology

Status

Published

Research group

  • Drug Target Discovery

ISBN/ISSN/Other

  • ISSN: 1540-658X