Abstract
G protein-coupled receptors (GPCRs) make up the largest receptor family in humans, which also constitute principal molecular targets for about 36% of approved drugs. Recent studies show that GPCRs can form heteromeric complexes with new molecular features. Little, however, is known about how human bitter taste receptors (T2Rs) form heteromeric receptors with other GPCRs. In this study, we combine biomolecular fluorescence complementation assays with methods for chemiluminescence imaging of cells, and find that β2-adrenergic receptor (β2AR) interacts with a subset of T2Rs, including T2R10, T2R14, T2R38, and T2R44, but selectively promotes cell membrane localization of only T2R14, T2R38, and T2R44. Furthermore, in silico modeling, coimmunoprecipitation, and immunofluorescence analysis indicate that β2AR utilizes distinct interfacial domains to interact with different T2Rs. And the β2AR-T2R14 interaction is selectively disrupted by a synthetic peptide corresponding to the transmembrane helix 4 of β2AR, which, however, does not block ligand-induced β2AR or T2R14 receptor internalization. Taken together, our findings demonstrate that β2AR employs different transmembrane helices to interact with and regulate special T2R subtypes. The insights obtained from this research may further our understanding of the β2AR-T2R interaction mechanisms and facilitate the development of new clinical drugs targeting β2AR-T2R complexes.