title: Shifts in the affinity distribution of one class of seven-transmembrane receptors by activation of a separate class of seven-transmembrane receptors.
abstract: We have demonstrated previously that activation of thrombin receptors causes increased Galpha(q) coupling to thromboxane A(2) receptors and increased thromboxane A(2) receptor ligand affinity. These results led to the hypothesis that thrombin receptor activation stimulates Galpha(q) redistribution to thromboxane A(2) receptors, thereby shifting them to a higher affinity state. The present study investigated three questions regarding this inter-receptor signaling phenomenon: (i) does activation of thrombin receptors cause a redistribution of thromboxane A(2) receptor subpopulations; (ii) does inter-receptor signaling require that participating receptors couple to the same family of G-protein alpha-subunits; and (iii) does inter-receptor signaling occur in cell types other than platelets? It was found that thrombin receptor activation caused a shift in the thromboxane A(2) receptor binding data from a one-site model to a two-site model (K(i) = 0.5 microM vs K(i) = 10 nM and 1.1 microM for the antagonist 4-[2-[[(4-chlorophenyl)sulfonyl]amino]ethyl]benzeneacetic acid (BM13. 505) and K(i) = 2.5 microM vs K(i) = 29.5 nM and 2.6 microM for the agonist 9,11-dideoxy-9alpha,11alpha-methanoepoxy prostaglandin F(2alpha) (U46619). It also was found that activation of prostaglandin D(2) receptors also caused a shift of prostacyclin receptor binding data from a one-site model (IC(50) = 10.1 nM) to a two-site model (IC(50) = 3.3 and 12.5 nM). The physiological manifestation of this inter-receptor signaling between prostacyclin and prostaglandin D(2) receptors was a synergistic inhibition of human platelet aggregation. Finally, the present results established that activation of endothelial cell thrombin receptors shifts thromboxane A(2) receptor affinity from K(i) = 0.8 microM (control) to K(i) = 0.2 microM (thrombin receptor-activating peptide), indicating that cells other than platelets have the capability to signal between seven-transmembrane receptors.
authors.affiliation: Department of Pharmacology, University of Illinois at Chicago, Chicago, IL, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Djellas
authors.forename: K
authors.initials: K
authors.lastname: Antonakis
authors.forename: G C
authors.initials: GC
authors.lastname: Le Breton
mesh_terms: D001792:Blood Platelets / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D008168:Lung / Q000166:cytology / Q000378:metabolism; D010974:Platelet Aggregation; D018179:Receptors, Thrombin / Q000378:metabolism*; D017482:Receptors, Thromboxane / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D008024:Ligands; D018179:Receptors, Thrombin; D017482:Receptors, Thromboxane; D019204:GTP-Binding Proteins