Article (Scientific journals)
Multiscale model of dynamic neuromodulation integrating neuropeptide-induced signaling pathway activity with membrane electrophysiology.
Makadia, Hirenkumar K.; Anderson, Warren D.; Fey, Dirk et al.
2015In Biophysical Journal, 108 (1), p. 211-23
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Abstract :
[en] 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 Ca(2+) signaling. Our model simulations revealed a baseline Ca(2+)-dependent response to AngII receptor type-1 activation by AngII. Consistent with experimental observations, AngII evoked a rise in Ca(2+) when starting at a low baseline Ca(2+) level, and a decrease in Ca(2+) when starting at a higher baseline. Our analysis predicted that the kinetics of Ca(2+) transport into the endoplasmic reticulum play a critical role in shaping the Ca(2+) response. The Ca(2+) baseline also influenced the AngII-induced excitability changes such that lower Ca(2+) levels were associated with a larger firing rate increase. We examined the relative contributions of signaling kinases protein kinase C and Ca(2+)/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 Ca(2+)/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.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Makadia, Hirenkumar K.
Anderson, Warren D.
Fey, Dirk
SAUTER, Thomas ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
Schwaber, James S.
Vadigepalli, Rajanikanth
Language :
English
Title :
Multiscale model of dynamic neuromodulation integrating neuropeptide-induced signaling pathway activity with membrane electrophysiology.
Publication date :
2015
Journal title :
Biophysical Journal
ISSN :
1542-0086
Publisher :
Biophysical Society, United States - Maryland
Volume :
108
Issue :
1
Pages :
211-23
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
Copyright (c) 2015 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Available on ORBilu :
since 09 January 2015

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