Both Ligand- and Cell-Specific Parameters Control Ligand Agonism in a Kinetic Model of G Protein–Coupled Receptor Signaling
Figure 6
Protean Agonism in the α2A-Adrenergic System
(A) Effect of levomed on cAMP production. Note that the y-axis in this plot is inverted from the usual to show positive agonists to have a positive slope and inverse agonists to have a negative slope. Levomed acts as an inverse agonist in HEL 92.1.7 cells (•, with curve fit). Data taken from Jansson et al. (1998), Figure 4. Levomed acts as a positive agonist in PC12 cells (line only). Data reconstructed from EC50 and max percent inhibition reported in Jansson et al. (1994), Table 1.
(B–D) Simulations of protean agonism of levomed at the α2A-adrenergic receptor. Small changes in parameter values can cause the response to switch from positive to negative.
(B) 3.3-Fold variation in G protein expression, β = 10.
(C) A 4-fold variation in the G protein activation rate constant kGact, Gtotal = 100,000.
(D) The equilibrium ratio of active to inactive receptors is varied 5-fold, Gtotal = 10,000, kGact = 5 s−1. Parameter values are equal to those listed in Figure 5 except when otherwise noted. Rtotal = 3,500 number/cell. Simulated dose response curves (B–D) measuring the percent accumulation of GαGTP (%Accum) were calculated according to Equation 2 as described in Methods.