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J. Biol. Chem., Vol. 279, Issue 21, 22102-22107, May 21, 2004

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Spontaneous Formation of a Proteolytic B1 and B2 Bradykinin Receptor Complex with Enhanced Signaling Capacity^*

Dong Soo Kang, Kristina Ryberg, Matthias Mörgelin¶, and L. M. Fredrik Leeb-Lundberg||

From the Division of Molecular Neurobiology, Department of Physiological Sciences and ^¶Division of Molecular Pathogenesis, Department of Cell and Molecular Biology, Lund University, Lund SE-22184, Sweden and Department of Biochemistry, The University of Texas Health Science Center, San Antonio, Texas 78229-3900

B1 bradykinin receptor (B1R) induction is critical in the adaptation of the kinin-mediated inflammatory response from a B2 bradykinin receptor (B2R) subtype to a B1R subtype that occurs during chronic insult. Here, we show that B1R spontaneously forms a proteolytic plasma membrane complex with B2R along with increased receptor signaling capacity. Co-expression of hemagglutinin-tagged B2R with FLAG-tagged B1R in HEK293 cells resulted in degradation of B2R as determined by the diminution of the intact 65-kDa B2R species and the appearance of proteolytic B2R products at 30–40 kDa and by the reduction in B2R bradykinin binding sites. On the other hand, the 35-kDa B1R remained intact. Receptor co-expression also led to an increase in constitutive and agonist-stimulated receptor signaling. Selective immunoprecipitation with epitope-specific antibodies revealed a spontaneously formed heterologous receptor complex, which was composed of the intact 35-kDa B1R and the B2R degradation products. Cellular fractionation, cell surface biotinylation, and immunoelectron microscopy showed that B2R·B1R complexes were present on the cell surface. This is the first evidence that a heterologous G protein-coupled receptor complex in the plasma membrane is linked to proteolytic degradation of a participating receptor, and this mechanism may contribute to the adaptation of the kinin response from a B2 type to a B1 type during chronic insult.

Received for publication, March 8, 2004

^* This work was supported by National Institutes of Health Grant GM41659, the Swedish Research Council, Alfred Österlunds Stiftelse, Crafordska Stiftelsen, Konung Gustav V:s 80-årsfond, Kocks Stiftelser, and the Faculty of Medicine, Lund University. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^|| To whom correspondence should be addressed: Division of Molecular Neurobiology, Wallenberg Neuroscience Center, Lund University, BMC, A12, Sölvegatan 17, SE-22184 Lund, Sweden. Tel.: 46-46-2223944; Fax: 46-46-2220568; E-mail: fredrik.leeb-lundberg{at}mphy.lu.se.

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