Integrated signaling and electrophysiological model of angiotensin II induced neuronal adaptation in the brain

Abstract

In this study, we focus on the multi-scale dynamics involved in neuronal adaptation at two levels: signaling dynamics elicited by neuropeptide receptors and the consequences on the electrophysiology. The particular system considered is the angiotensin II receptor type 1 (AT1R) signaling and electrical activity in the cardiorespiratory neurons in the Nucleus Tractus Solitarius (NTS) in the brainstem. We have developed a multi-scale mathematical model that integrates a Hodgkin-Huxley like model of the electrophysiology and a detailed kinetic reaction model of the AT1R mediated intracellular signaling pathway. The key aspect of the integrated model is the change in conductance of different ion channels upon phosphorylation by the signaling kinases. Analysis of the model dynamics revealed distinct regulatory properties corresponding to different ion channels, a novel role for the delayed rectifier potassium channel as a dual regulator, and counteracting effects of non-voltage-activated transport and ion channel phosphorylation resulting in a net increase in neuronal firing rate, in concordance with experimental data. Research Support: NIH/HLB R33 HL087361 and NIH/NIAAA R01 AA13204 to JSS.