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 A(2) receptors. Activation of thrombin receptors caused an increase in ligand affinity of thromboxane A(2) 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 G(αq) C terminus antibody; and (iv) was associated with a net increase in G(αq) coupling to thromboxane A(2) receptors. Collectively, these data provide evidence that seven-transmembrane receptors that share a common G(α) subunit can communicate with each other via a redistribution of their G proteins. Thus, activation of thrombin receptors increases G(αq) association with thromboxane A(2) 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.