This study represents the first attempt to couple, by computational experiments, the mechanisms of intramolecular and intermolecular communication concerning a guanicline nucleoticle exchange factor (GEF), the throrhboxane A2 receptor (TXA(2)R), and the cognate G protein (Gq) in its heterotrimeric GDP-bound state. Two-way pathways mediate the communication between the receptor-G protein interface and both the agonist binding site of the receptor and the nucleotide binding site of the G protein. The increase in solvent accessibility in the neighborhoods of the highly conserved E/DRY receptor motif, in response to agonist binding, is instrumental in favoring the penetration of the C-terminus of Gq, in between the cytosolic ends of H3, H5, and H6. The arginine of the E/DRY motif is predicted to be an important mediator of the intramolecular and intermolecular communication involving the TXA2R. The receptor-G protein interface is predicted to involve multiple regions from the receptor and the G protein a-subunit. However, receptor contacts with the C-terminus of the alpha 5-helix seem to be the major players in the receptor-catalyzed motion of the a-helical domain with respect to the Ras-like domain and in the formation of a nucleoticle exit route in between the alpha F-helix and beta 6/alpha 5 loop of Gq alpha. The inferences from this study are of wide interest, as they are expected to apply to the whole rhodopsin family, given also the considerable G protein promiscuity.