Multi-scale modeling of angiotensin II induced neuronal regulatory mechanisms in the brain
© Vadigepalli et al; licensee BioMed Central Ltd. 2008
Published: 11 July 2008
In this study, we focus on the multi-scale dynamics involved in neuronal regulatory mechanisms at two levels: signaling dynamics elicited by neuropeptide receptors and their crosstalk with the electrophysiological processes. The particular system considered is the angiotensin II (AngII) receptor type 1 (AT1R) signaling and modulation of electrical activity in the cardiorespiratory control neurons in the brainstem. AngII acting via AT1R in the brainstem influences the baroreceptor reflexes thus modulating cardiac and respiratory homeostasis. Stimulation of brainstem neurons by AngII has been shown to result in dynamic changes in excitability, a neuronal adaptation lasting several minutes, and this response is mediated by AT1R activated by AngII .
We have developed a multi-scale mathematical model that integrates a detailed kinetic reaction model of the AT1R mediated signaling pathway with a Hodgkin-Huxley-like model of the membrane electrophysiology. Our model includes Gq-protein-mediated activation of Ca2+-dependent enzymes Protein Kinase C (PKC) and Calcium/calmodulin-dependent protein kinase II (CaMKII). The electrical model contains channels that are relevant to cardiorespiratory neurons in the brainstem . The key aspects of the integrated model include: (1) change in the conductance of potassium channels upon phosphorylation by PKC and CaMKII, (2) voltage dependence of Na+-Ca2+ exchanger, and (3) compartmentalized Ca2+ balance accounting for signaling-mediated and voltage-dependent mechanisms. The parameters were identified either by fitting to experimental data summarized in , or via sensitivity analyses searching for robust parameter ranges.
Research Support: NIH/HLB R33 HL087361 to JSS
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