THE EFFECT OF THE MOLECULAR MECHANISM OF G-PROTEIN-COUPLED RECEPTOR ACTIVATION ON THE PROCESS OF SIGNAL-TRANSDUCTION

A thermodynamic model of signal transduction that incorporates the pos sibility of multiple conformational states between the inactive and th e active forms of the receptor was developed. The obtained equilibrium model is equivalent to the extended ternary complex of Samama et al. (J. Biol. Chem. 268 (1993) 4625-4636) if only two states of the recept or exist. These multiple equilibria between receptor states are modele d by two sets of equilibrium constants: K-Pi AR and K-Sigma Pi AR, in the presence of the Ligand; and K-Pi R and K-Sigma Pi R, in the absenc e of the ligand. The higher the value of these constants, the more eff iciently the active form of the receptor is generated. Intrinsic effic acy of the agonist is defined in the present formulation as the molecu lar processes induced by ligands in the receptor that lead to the acti ve form of the receptor. Both the energetics (associated to K-Pi AR) a nd mechanism of the process of receptor activation (associated to K-Pi AR) are important in eliciting the maximum response. Moreover, analyt ical expressions of basal activity, potency and maximum response were obtained. These definitions were used to classify the extra cellular l igand as agonists (K-Sigma Pi AR > K-Sigma Pi R), inverse agonists(K-S igma Pi R > K-Sigma Pi AR > 0), neutral antagonists (K-Sigma Pi AR = K -Sigma Pi R), and pure antagonists. (C) 1997 Elsevier Science B.V.