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Originally published In Press as doi:10.1074/jbc.M007396200 on December 27, 2000

J. Biol. Chem., Vol. 276, Issue 12, 8785-8792, March 23, 2001
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The Human B1 Bradykinin Receptor Exhibits High Ligand-independent, Constitutive Activity
ROLES OF RESIDUES IN THE FOURTH INTRACELLULAR AND THIRD TRANSMEMBRANE DOMAINS*

L. M. Fredrik Leeb-LundbergDagger , Dong Soo Kang, Maria E. Lamb, and Dana B. Fathy

From the Department of Biochemistry, the University of Texas Health Science Center, San Antonio, Texas 78229-3900

The B1 bradykinin (BK) receptor (B1R) is a seven-transmembrane domain, G protein-coupled receptor that is induced by injury and important in inflammation and nociception. Here, we show that the human B1R exhibits a high level of ligand-independent, constitutive activity. Constitutive activity was identified by the increase in basal cellular phosphoinositide hydrolysis as a function of the density of the receptors in transiently transfected HEK293 cells. Several B1R peptide antagonists were neutral antagonists or very weakly efficacious inverse agonists. Constitutive B1R activity was further increased by alanine mutation of Asn121 in the third transmembrane domain of the receptor (B1A121). This mutant resembled the agonist-preferred receptor state since it also exhibited increased agonist affinity and decreased agonist responsiveness. A dramatic loss of constitutive activity occurred when the fourth intracellular C-terminal domain (IC-IV) of the human B2 BK receptor subtype (B2R), which exhibits minimal constitutive activity, was substituted in either B1R or B1A121 to make B1(B2ICIV) and B1(B2ICIV)A121, respectively. Activity was partially recovered by subsequent alanine mutation of a cluster of two serines and two threonines in IC-IV of either B1(B2ICIV) or B1(B2ICIV)A121, a cluster that is important for B2R desensitization. The ligand-independent, constitutive activity of B1R therefore depends on epitopes in both transmembrane and intracellular domains. We propose that the activity is primarily due to the lack of critical epitopes in IC-IV that regulate such activity.

* This work was supported by National Institutes of Health Grant GM41659.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Biochemistry, the University of Texas Health Science Center, Mail Code 7760, 7703 Floyd Curl Dr., San Antonio, TX 78229-3900. Tel.: 210-567-3766; Fax: 210-567-6595; E-mail: lundberg@biochem.uthscsa.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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