Three modified mathematical models simulating PtdIns(4,5)P₂ regeneration during receptor activation. All curves are simulations with receptor activation during the shaded areas. (A–O) Comparison of the assumption of PI4K acceleration (A–E), PIP5K acceleration (F–J), or PLC desensitization (K–O) as explanations of PtdIns(4,5)P₂ regeneration. All models consider only the steps with black arrows in Fig. 1, and they assume that the concentration of PtdIns at the PM remains constant. (A, F, and K) Panels show the range of hypothetical time courses tested for the kinetics of PI4K, PI5K, or PLC, respectively. They are evaluated by the simulations in the four panels to the right of them. (A–E) Progressive acceleration of PI4K during 10-µM Oxo-M stimulation. (A) Assumed accelerations of the rate of PI4K in the first model during M₁R activation, ranging from the standard Falkenburger model (green curve) to increasing accelerations (violet, red, and black). (B–E) The predicted concentrations of PM PtdIns4P (B) and PtdIns(4,5)P₂ (C), Ins(1,4,5)P₃ interacting with LIBRAvIII (D), and DAG interacting with C1A domains (E), color-coded as in A. (F–J) Progressive acceleration of PIP5K during 10-µM Oxo-M stimulation, shown in the same format as A–E. (K–O) Progressive slowing of PLC activity during 10-µM Oxo-M stimulation.