Hansen_2013_PLoS.One_8_e58890

BACKGROUND: Functional cross-talk between seven transmembrane (7TM) receptors can dramatically alter their pharmacological properties, both in vitro and in vivo. This represents an opportunity for the development of novel therapeutics that potentially target more specific biological effects while causing fewer adverse events. Although several studies convincingly have established the existence of 7TM receptor cross-talk, little is known about the frequencey and biological significance of this phenomenon. METHODOLOGY/PRINCIPAL FINDINGS: To evaluate the extent of synergism in 7TM receptor signaling, we took a comprehensive approach and co-expressed 123 different 7TM receptors together with the angiotensin II type 1 receptor (AT1R) and analyzed how each receptor affected the angiotensin II (AngII) response. To monitor the effect we used integrative receptor activation/signaling assay called Receptor Selection and Amplification Technology (R-SAT). In this screen the thromboxane A2alpha receptor (TPalphaR) was the only receptor which significantly enhanced the AngII-mediated response. The TPalphaR-mediated enhancement of AngII signaling was significantly reduced when a signaling deficient receptor mutant (TPalphaR R130V) was co-expressed instead of the wild-type TPalphaR, and was completely blocked both by TPalphaR antagonists and COX inhibitors inhibiting formation of thromboxane A2 (TXA2). CONCLUSIONS/SIGNIFICANCE: We found a functional enhancement of AT1R only when co-expressed with TPalphaR, but not with 122 other 7TM receptors. In addition, the TPalphaR must be functionally active, indicating the AT1R enhancement is mediated by a paracrine mechanism. Since we only found one receptor enhancing AT1R potency, our results suggest that functional augmentation through 7TM receptor cross-talk is a rare event that may require specific conditions to occur.