Multiscale Model of Dynamic Neuromodulation Integrating Neuropeptide-Induced Signaling Pathway Activity with Membrane Electrophysiology

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Title: Multiscale Model of Dynamic Neuromodulation Integrating Neuropeptide-Induced Signaling Pathway Activity with Membrane Electrophysiology
Authors: Makadia, Hirenkumar K.
Anderson, Warren D.
Fey, Dirk
et al.
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Date: 6-Jan-2015
Abstract: We developed a multiscale model to bridge neuropeptide receptor-activated signaling pathway activity with membrane electrophysiology. Typically, the neuromodulation of biochemical signaling and biophysics have been investigated separately in modeling studies. We studied the effects of Angiotensin II (AngII) on neuronal excitability changes mediated by signaling dynamics and downstream phosphorylation of ion channels. Experiments have shown that AngII binding to the AngII receptor type-1 elicits baseline-dependent regulation of cytosolic Ca2+ signaling. Our model simulations revealed a baseline Ca2+-dependent response to AngII receptor type-1 activation by AngII. Consistent with experimental observations, AngII evoked a rise in Ca2+ when starting at a low baseline Ca2+ level, and a decrease in Ca2+ when starting at a higher baseline. Our analysis predicted that the kinetics of Ca2+ transport into the endoplasmic reticulum play a critical role in shaping the Ca2+ response. The Ca2+ baseline also influenced the AngII-induced excitability changes such that lower Ca2+ levels were associated with a larger firing rate increase. We examined the relative contributions of signaling kinases protein kinase C and Ca2+/Calmodulin-dependent protein kinase II to AngII-mediated excitability changes by simulating activity blockade individually and in combination. We found that protein kinase C selectively controlled firing rate adaptation whereas Ca2+/Calmodulin-dependent protein kinase II induced a delayed effect on the firing rate increase. We tested whether signaling kinetics were necessary for the dynamic effects of AngII on excitability by simulating three scenarios of AngII-mediated KDR channel phosphorylation: (1), an increased steady state; (2), a step-change increase; and (3), dynamic modulation. Our results revealed that the kinetics emerging from neuromodulatory activation of the signaling network were required to account for the dynamical changes in excitability. In summary, our integrated multiscale model provides, to our knowledge, a new approach for quantitative investigation of neuromodulatory effects on signaling and electrophysiology.
Type of material: Journal Article
Publisher: Elsevier
Journal: Biophysical Journal
Volume: 108
Issue: 1
Start page: 211
End page: 223
Copyright (published version): 2015 Biophysical Society
Keywords: AngII signalingElectrophysiology
DOI: 10.1016/j.bpj.2014.11.1851
Language: en
Status of Item: Peer reviewed
Appears in Collections:SBI Research Collection

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