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Multi‐scale modeling of neuronal adaptation mediated by angiotensin II in the central regulation of blood pressure
Author(s) -
Vadigepalli Rajanikanth,
Nikolaev Evgeni,
Miller Gregory M,
Ogunnaike Babatunde,
Gonye Gregory,
Kholodenko Boris,
Schwaber James S
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.756.2
Subject(s) - angiotensin ii , neuroscience , tyrosine hydroxylase , homeostasis , biology , microbiology and biotechnology , chemistry , endocrinology , blood pressure , dopamine
In this study, we focus on the modulation of brainstem cardiorespiratory neurons via angiotensin II receptor, type 1 (AT1R) activation, leading to short‐term consequences on the electrophysiology, and long‐term effects on gene expression. Disregulation of these processes in CNS neurons contributes to several diseases involving homeostasis, most notably hypertension. Our approach is to develop and analyze a multi‐scale mathematical model integrating signaling, gene regulation and electrophysiology in order to identify key mechanisms playing a role in the immediate changes in excitability as well as those involved in long lasting effects on synthesis and release of norepinephrine (NE), a key neurotransmitter involved in cardiovascular regulation. Our model includes detailed kinetics of Gq, PKC, MAPK and PI3K pathways, activation of an immediate early transcription factor AP‐1, and a Hodgkin‐Huxley like description of electrophysiology. Analysis of the model structure and dynamics revealed contributions of multiple mechanisms for activation of AP‐1 leading to novel hypotheses on a dynamic balance between c‐fos and c‐jun activation as an alternative mechanism for transcriptional regulation of Tyrosine Hydroxylase, a rate‐limiting enzyme in the synthesis of NE. Research Support: NIH/HLB R33 HL087361 to JSS and BK.