title: Multiscale model of dynamic neuromodulation integrating neuropeptide-induced signaling pathway activity with membrane electrophysiology.
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 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.
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Hirenkumar K
authors.initials: HK
authors.lastname: Makadia
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; Graduate Program in Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: Warren D
authors.initials: WD
authors.lastname: Anderson
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin, Ireland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Fey
authors.affiliation: Life Sciences Research Unit, University of Luxembourg, Walferdange, Luxembourg.
authors.forename: Thomas
authors.initials: T
authors.lastname: Sauter
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; Graduate Program in Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania.
authors.forename: James S
authors.initials: JS
authors.lastname: Schwaber
authors.affiliation: Daniel Baugh Institute for Functional Genomics and Computational Biology, Department of Pathology, Anatomy and Cell Biology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; Graduate Program in Neuroscience, Thomas Jefferson University, Philadelphia, Pennsylvania. Electronic address: rajanikanth.vadigepalli@jefferson.edu.
authors.forename: Rajanikanth
authors.initials: R
authors.lastname: Vadigepalli
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology*; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D044140:Receptor, Angiotensin, Type 1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007473:Ion Channels; D009479:Neuropeptides; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium