Figure 1.

Integrated model of the intracellular signaling and electrophysiology. (A) An overview of the integrated model topology, showing AngII activation eliciting multiple signaling pathways and subsequently modulating membrane electrophysiology. (B) Circuit diagram of the electrophysiology model. (C) Schematic depicting the phosphorylation reactions underlying the AngII-mediated reduction of K_DR conductance. (D) Plot showing the fractional reduction of unphosphorylated K_DR channels as a function of phosphorylation/dephosphorylation reaction rate ratios (k_p/k_dp for both PKC and CaMKII). Data correspond to simulations in which K_U^ss indicates the fraction of unphosphorylated K_DR channels after 100 nM AngII at steady state and K_Uⁱ refers to the fraction of unphosphorylated K_DR channels before the application of AngII. The relative phosphorylation and dephosphorylation rates were set to yield ∼30% reduction in unphosphorylated channels to fit the experimental data in (E) (see Table S4 for reaction details). (E) Model fit to dynamic K_DR current data after the application of 100 nM AngII to cultured brainstem neurons (37). (F) I-V relations for K_DR from experiments (37) and simulations under baseline conditions and after 100 nM AngII application to cultured brainstem neurons.