Transactivation of Beta 2 Adrenergic Receptor by Bradykinin Receptor via Heterodimerization

Abstract

G Protein‐coupled receptors (GPCRs) are the third largest family of genes in the human genome and are the target of many pharmaceuticals. Evidence has shown that many GPCRs form heteromeric complexes, although the functional consequences of such interactions are unclear. Bradykinin type 2 receptor (Bk2R) and Beta 2 adrenergic receptor ( β2AR), Gαq‐ and Gαs‐coupled receptors, respectively, are GPCRs that can heterodimerize with other members of their classes in vitro and in vivo, participate in cardiovascular regulation, and are coexpressed in many cell types, including pheochromocytoma (PC12) cells. Given these factors, we examined potential interplay between Bk2R and β2AR. We hypothesized that Bk2R and β2AR physically associate, changing native receptor signaling. Co‐immunoprecipitation studies in PC12 cells and X. laevis oocytes showed physical association of Bk2R and β2AR. In both PC12 cells and oocytes expressing these receptors, bradykinin‐induced Bk2R transactivation via both Gαs‐ and Gαq‐coupled pathways, which was significantly ablated by inverse agonists of Bk2R or β2AR; thus, conformational changes in both receptors are required for transactivation. This is the first evidence of Bk2R/β2AR physical interaction and functional cross‐talk. Given the relevance of pharmaceutics that affect Bk2R and β2AR, these exciting data may provide opportunities for drug development and refinement.