title: Functional enhancement of AT1R potency in the presence of the TPαR is revealed by a comprehensive 7TM receptor co-expression screen.
abstract: 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.
  
  
  RESULTS
  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 A2α receptor (TPαR) was the only receptor which significantly enhanced the AngII-mediated response. The TPαR-mediated enhancement of AngII signaling was significantly reduced when a signaling deficient receptor mutant (TPαR R130V) was co-expressed instead of the wild-type TPαR, and was completely blocked both by TPαR antagonists and COX inhibitors inhibiting formation of thromboxane A2 (TXA2).
  
  
  CONCLUSIONS
  We found a functional enhancement of AT1R only when co-expressed with TPαR, but not with 122 other 7TM receptors. In addition, the TPαR 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.
authors.affiliation: Laboratory for Molecular Cardiology, Department of Biomedical Sciences and The Danish National Research Foundation Centre for Cardiac Arrhythmia, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Jonas Tind
authors.initials: JT
authors.lastname: Hansen
authors.forename: Christina
authors.initials: C
authors.lastname: Lyngsø
authors.forename: Tobias
authors.initials: T
authors.lastname: Speerschneider
authors.forename: Pernille B L
authors.initials: PB
authors.lastname: Hansen
authors.forename: Céline
authors.initials: C
authors.lastname: Galés
authors.forename: David M
authors.initials: DM
authors.lastname: Weiner
authors.forename: Søren P
authors.initials: SP
authors.lastname: Sheikh
authors.forename: Ethan S
authors.initials: ES
authors.lastname: Burstein
authors.forename: Jakob Lerche
authors.initials: JL
authors.lastname: Hansen
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002417:Cattle; D002460:Cell Line; D015870:Gene Expression; D006801:Humans; D019899:Paracrine Communication / Q000187:drug effects; D020239:Receptor Cross-Talk / Q000187:drug effects; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism*; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
chemical_list: D044140:Receptor, Angiotensin, Type 1; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D000804:Angiotensin II