Hetero-oligomerization between adenosine A₁ and thromboxane A₂ receptors and cellular signal transduction on stimulation with high and low concentrations of agonists for both receptors.
Growing evidence indicates that G protein-coupled receptors can form homo- and hetero-oligomers to diversify signal transduction. However, the molecular mechanisms and physiological significance of G protein-coupled receptor-oligomers are not fully understood. Both ADOR1 (adenosine A(1) receptor) and TBXA2R (thromboxane A(2) receptor α; TPα receptor), members of the G protein-coupled receptor family, act on astrocytes and renal mesangial cells, suggesting certain functional correlations. In this study, we explored the possibility that adenosine A(1) and TPα receptors form hetero-oligomers with novel pharmacological profiles. We showed that these receptors hetero-oligomerize by conducting coimmunoprecipitation and bioluminescence resonance energy transfer (BRET(2)) assays in adenosine A(1) receptor and TPα receptor-cotransfected HEK293T cells. Furthermore, coexpression of the receptors affected signal transduction including the accumulation of cyclic AMP and phosphorylation of extracellular signal-regulated kinase-1 and -2 was significantly increased by high and low concentrations of adenosine A(1) receptor agonist and TPα agonists, respectively. Our study provides evidence of hetero-oligomerization between adenosine A(1) and TPα receptors for the first time, and suggests that this oligomerization affects signal transduction responding to different concentrations of receptor agonists.
Department of Cellular Signaling, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Natsumi
N
Mizuno
Tokiko
T
Suzuki
Noriyasu
N
Hirasawa
Norimichi
N
Nakahata
D058907:Adenosine A1 Receptor Agonists / Q000494:pharmacology*; D020013:Calcium Signaling / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D043682:Receptor, Adenosine A1 / Q000737:chemistry* / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000819:agonists* / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D058907:Adenosine A1 Receptor Agonists; D043682:Receptor, Adenosine A1; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D005576:Colforsin; D000242:Cyclic AMP; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3