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Am J Physiol Heart Circ Physiol 284: H1909-H1916, 2003; doi:10.1152/ajpheart.00034.2003
0363-6135/03 $5.00
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Vol. 284, Issue 6, H1909-H1916, June 2003

SPECIAL TOPICS
Regulation of Cardiovascular Signaling by Kinins and Products of Similar Converting Enzyme Systems
Downregulation of bradykinin B2 receptor in human fibroblasts during prolonged agonist exposure

Andree Blaukat1, Patrick Micke4, Irina Kalatskaya3, Alexander Faussner3, and Werner Müller-Esterl2

1 Institute of Pharmacology, University of Heidelberg, D-69120 Heidelberg; 2 Institute for Biochemistry II, University of Frankfurt Medical School, D-60590 Frankfurt; 3 Institute for Clinical Chemistry and Clinical Biochemistry, University of Munich, D-80336 Munich, Germany; and 4 Ludwig Institute for Cancer Research, S-75124 Uppsala, Sweden

Sustained activation of G protein-coupled receptors results in an attenuation of cellular responses, a phenomenon termed desensitization. Whereas mechanisms for rapid desensitization of ligand-receptor-G protein-effector systems are relatively well characterized, much less is known about long-term adaptation processes that occur in the continuous presence of an agonist. Here we have studied the fate of endogenously expressed bradykinin B2 receptors on human fibroblasts during prolonged agonist treatment. Stimulation with bradykinin for up to 24 h resulted in a 50% reduction of surface binding sites that was paralleled by a similar decrease of total B2 receptor protein followed by Western blotting using monoclonal antibodies to the B2 receptor. Whereas B2 receptor mRNA levels did not change during 24 h of agonist treatment, B2 receptor de novo synthesis was attenuated by 35-50%, indicating translational control of B2 receptor levels. Furthermore, the half-life of B2 receptor protein was shortened by 20-40% as shown by 35S-labeled pulse-chase and immunoprecipitation experiments. This study demonstrates that bradykinin B2 receptor expression during long-term agonist treatment is primarily regulated on the (post)translational level, i.e., by attenuation of de novo synthesis and by reduction of receptor stability.

G protein-coupled receptor; sequestration; monoclonal antibody


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