Fig. 3.

Simulation of the effects of partial inactivation of the receptor population with an irreversible neutral antagonist on the response to an agonist (a) and an inverse agonist (b). The theoretical curves were generated using the operational model for the total stimulus (eq. 27) with the latter defined as the summation of the active states of the quaternary (DR_s*GX) and ternary (R_s*GX) complexes. These were simulated using the quaternary complex model described in Ehlert et al. (2011). The values of log K_a and log K_b for the orthosteric ligands were: agonist, 5.0 and 8.0; inverse agonist, 7.0 and 5.0, respectively. The microscopic state constants for the quaternary complex model were: log K_e, −2.15; log K_g, 2.85; log K_k, 8.00; log K_m, 4.60, and log K_c, −4.30. The ratio of G protein to receptor was 10, and the receptor concentration was 40 units. These parameters yield a quaternary complex (DR_s*GX) function with a log K_obs of 5.08. The parameters of the operational model were M_sys, 100; m, 1.0; and log K_E, −1.7.