Functional enhancement of AT1R potency in the presence of the TPaR is revealed by a comprehensive 7TM receptor co-expression screen.

PloS one

PubMedID: 23516570

Hansen JT, Lyngsø C, Speerschneider T, Hansen PB, Galés C, Weiner DM, Sheikh SP, Burstein ES, Hansen JL. Functional enhancement of AT1R potency in the presence of the TPaR is revealed by a comprehensive 7TM receptor co-expression screen. PLoS ONE. 2013;8(3):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 A2a receptor (TPaR) was the only receptor which significantly enhanced the AngII-mediated response. The TPaR-mediated enhancement of AngII signaling was significantly reduced when a signaling deficient receptor mutant (TPaR R130V) was co-expressed instead of the wild-type TPaR, and was completely blocked both by TPaR antagonists and COX inhibitors inhibiting formation of thromboxane A2 (TXA2).

CONCLUSIONS/SIGNIFICANCE
We found a functional enhancement of AT1R only when co-expressed with TPaR, but not with 122 other 7TM receptors. In addition, the TPaR 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.