BIOPHYSICAL THEORY AND MODELING |
Mathematical and Computational Analysis of Adaptation via Feedback Inhibition in Signal Transduction Pathways
Marcelo Behar 1, Nan Hao 2, Henrik G Dohlman 1 and Timothy C Elston 3*
1 University of North Carolina
2 Univeristy of North Carolina
3 University of North Carolina at Chapel Hill
* To whom correspondence should be addressed. E-mail: telston{at}amath.unc.edu.
Submitted on February 23, 2007
Revised on March 29, 2007
Accepted on 12 April 2007
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Abstract |
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We perform a systematic analysis of mechanisms of feedback regulation that underlie short-term adaptation in intracellular signaling systems. Upon receiving an external cue, these systems generate a transient response that quickly returns to basal levels even if the stimulus persists. Signaling pathways capable of short-term adaptation are found in systems as diverse as the high osmolarity response of yeast, gradient sensing in Dictyostelium, and the cytokine response in vertebrates. Using mathematical analysis and computational experiments we compare different feedback architectures in terms of response amplitude and duration, ability to adapt, and response to variable stimulus levels. Our analysis reveals three important features of these systems: 1) multiple step signaling cascades improve sensitivity to low doses by an effect distinct from signal amplification, 2) some feedback architectures act as signal transducers converting stimulus strength into response duration, and 3) feedback deactivation acts as a dose-dependent switch between transient and sustained responses. Finally, we present characteristic features for each form of feedback regulation that can aid in their identification.
Key Words:
adaptation, desensitization, feedback inhibition, intracellular signal transduction, mathematical modeling
