A molecular mechanism for signaling between seven-transmembrane receptors: evidence for a redistribution of G proteins.
Although activation of one seven-transmembrane receptor can influence the response of a separate seven-transmembrane receptor, e. g., the phenomenon of synergism, the underlying mechanism(s) for this signaling process is unclear. The present study investigated communication between two receptors that exhibit classical synergism, e.g., human platelet thrombin and thromboxane A2 receptors. Activation of thrombin receptors caused an increase in ligand affinity of thromboxane A2 receptors. This effect (i) was shown to be specific, since a similar increase in ligand affinity was not caused by ADP or A23187; (ii) did not require cytosolic components, e.g., kinases, proteases, phosphatases, etc., because it occurred in isolated platelet membranes; (iii) was G protein-mediated because it was blocked by an Galphaq C terminus antibody; and (iv) was associated with a net increase in Galphaq coupling to thromboxane A2 receptors. Collectively, these data provide evidence that seven-transmembrane receptors that share a common Galpha subunit can communicate with each other via a redistribution of their G proteins. Thus, activation of thrombin receptors increases Galphaq association with thromboxane A2 receptors thereby shifting them to a higher affinity state. This signaling phenomenon, which modulates receptor-ligand affinity, may serve as a molecular mechanism for cellular adaptive processes such as synergism.
Djellas
Y
Y
Department of Pharmacology, University of Illinois at Chicago, 835 S. Wolcott Ave. (mail code 868), Chicago, IL 60612, USA.
Antonakis
K
K
Le Breton
G C
GC
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011956:Receptors, Cell Surface / Q000378:metabolism*; D015398:Signal Transduction; D013917:Thrombin / Q000502:physiology; D013928:Thromboxane A2 / Q000502:physiology
D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C076901:thrombin receptor-activating peptide (P508-530); D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013917:Thrombin; D019204:GTP-Binding Proteins