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Am J Physiol Heart Circ Physiol (February 6, 2003). doi:10.1152/ajpheart.00033.2003
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Submitted on January 13, 2003
Accepted on January 30, 2003

Changes in the aminoterminal portion of humanB2 receptor selectively increase efficacy of synthetic ligand HOE140 but not of cognate ligand bradykinin

Christian Schroeder1, Andreas Breit2, Hilke Boning3, Jurgen Dedio4, Lajos Gera5, John Stewart5, and Werner Muller-Esterl6*

1 Institute for Cardiovascular and Arteriosclerosis Research, Bayer AG, Wuppertal, Germany
2 Institute for Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany; Department of Biochemistry, University of Montreal, Montreal, Canada
3 Department of Biochemistry, University of Montreal, Montreal, Canada; Department of Biochemistry, University of Munster, Munster, Germany
4 Institute for Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany; Department of Disease Group Research Frankfurt, Aventis, Frankfurt, Germany
5 Department of Biochemistry, University of Colorado Medical School, Denver, CO, USA
6 Institute for Biochemistry II, University of Frankfurt Medical School, Frankfurt, Germany

* To whom correspondence should be addressed. E-mail: wme{at}biochem2.de.

Recently we have shown that a widely used antagonist of the human bradykinin B2 receptor (B2R), HOEl4O, acts as a full agonist of the chicken ornithokinin receptor (B0R). To understand the molecular mechanisms underlying differential efficacy of HOE140 for the various kinin receptors we have constructed chimeric kinin receptors in which the aminoterminal portion including the first two transmembrane regions and the first extracellular loop (CKR-2) or only the second transmembrane region and the first extracellular loop (CKR-1) of B2R were substituted with the corresponding segments of B0R. Ligand efficacy of synthetic ligand HOE140 decreased in the order B0R > CKR-2 > CKR-1 > B2R whereas the efficacy of the endogenous kinin ligand was unchanged. Enhanced HOE140 efficacy was not due to a structural change in the ligand binding site or to an enhanced receptor expression level. Rather, heterologous binding competition studies indicated that structural change(s) introduced into the engineered receptors caused a selective reduction in apparent affinity of HOE140 for the uncoupled inactive receptor state R but not for the active G protein-coupled state R*, thereby increasing the ratio of R* over R for a given ligand concentration. Our results may help explain the unusually broad efficacy spectrum of HOE140 which varies from inverse to full agonism depending on kinin receptor subtype, tissue origin or species.




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 Am. J. Physiol. Heart Circ. Physiol.Home page
R. A. Skidgel, F. Alhenc-Gelas, and W. B. Campbell
Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems: Prologue: Kinins and related systems. New life for old discoveries
Am J Physiol Heart Circ Physiol, June 1, 2003; 284(6): H1886 - H1891.
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