To understand the dynamics of the AT1R mediated neuromodulation and the relative contribution of different kinases, we have developed an integrated model of AngII induced neuronal firing behavior. This multi-scale model integrates a Hodgkin-Huxley like model of the electrophysiology describing the millisecond dynamics of the ion channels and a detailed kinetic reaction model of the AT1R mediated intracellular signaling pathway. The membrane electrical model includes descriptions of different ion channels in the NTS neurons: sodium, delayed rectifier potassium, calcium activated potassium, high threshold L-type calcium, and leak channel. The signaling model was adapted from Mishra and Bhalla (Biophys J, 2002) by adding kinetic descriptions of receptor desensitization and the sodium-calcium exchanger. The modified model includes the dynamics of PLC, PKC, CaMKII, DAG, IP3 and intracellular calcium. The key aspect of integrating the signaling and electrical models is the change in the conductance of different ion channels upon phosphorylation by the kinases PKC and CamKII. The exact kinetics of this phosphorylation is not clear and hence different formulations of kinetic behavior were explored in the simulations. Analysis of the model dynamics revealed distinct regulatory properties corresponding to different ion channels and a novel role for the delayed rectifier potassium channel as a dual regulator. In addition, the simulations indicate that the non-voltage-activated transport dynamics lead to transient inhibition in response to AT1R stimulation. However, phosphorylation of the delayed rectifier potassium channel by PKC counteracts this transient inhibition to result in a net increase in the electrical activity, in concordance with the electrophysiological experimental observations.
The current model forms the basis for developing a multi-scale neuronal adaptation model that integrates electrophysiology, signaling and gene regulation.