title: Interpreting frequency responses to dose-conserved pulsatile input signals in simple cell signaling motifs.
abstract: Many hormones are released in pulsatile patterns. This pattern can be modified, for instance by changing pulse frequency, to encode relevant physiological information. Often other properties of the pulse pattern will also change with frequency. How do signaling pathways of cells targeted by these hormones respond to different input patterns? In this study, we examine how a given dose of hormone can induce different outputs from the target system, depending on how this dose is distributed in time. We use simple mathematical models of feedforward signaling motifs to understand how the properties of the target system give rise to preferences in input pulse pattern. We frame these problems in terms of frequency responses to pulsatile inputs, where the amplitude or duration of the pulses is varied along with frequency to conserve input dose. We find that the form of the nonlinearity in the steady state input-output function of the system predicts the optimal input pattern. It does so by selecting an optimal input signal amplitude. Our results predict the behavior of common signaling motifs such as receptor binding with dimerization, and protein phosphorylation. The findings have implications for experiments aimed at studying the frequency response to pulsatile inputs, as well as for understanding how pulsatile patterns drive biological responses via feedforward signaling pathways.
authors.affiliation: Department of Mathematics, Florida State University, Tallahasee, Florida, United States of America.
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Fletcher
authors.affiliation: Project-Team MYCENAE, Inria Paris-Rocquencourt Research Centre, Le Chesnay, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Clément
authors.affiliation: Laboratoire Analyse et Probabilités EA 2172, Université d'Évry-Val-d'Essonne, Evry, France; Project-Team MYCENAE, Inria Paris-Rocquencourt Research Centre, Le Chesnay, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Department of Mathematics and Department of Biological Science, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Joel
authors.initials: J
authors.lastname: Tabak
authors.affiliation: Department of Mathematics and Programs in Neuroscience and Molecular Biophysics, Florida State University, Tallahassee, Florida, United States of America.
authors.forename: Richard
authors.initials: R
authors.lastname: Bertram
mesh_terms: D000204:Activity Cycles; D000465:Algorithms; D002450:Cell Communication; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008954:Models, Biological; D010766:Phosphorylation; D011485:Protein Binding; D055503:Protein Multimerization; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D006728:Hormones; D008024:Ligands; D011956:Receptors, Cell Surface
references.citation: Diabetes. 1983 Jul;32(7):617-21
references.pmid: 6134649
references.citation: Science. 1978 Nov 10;202(4368):631-3
references.pmid: 100883
references.citation: Endocrinology. 1997 Mar;138(3):1224-31
references.pmid: 9048630
references.citation: Front Neuroendocrinol. 2009 Jan;30(1):10-29
references.pmid: 18708085
references.citation: J Theor Biol. 2002 Oct 21;218(4):457-70
references.pmid: 12384049
references.citation: Proc Natl Acad Sci U S A. 1981 Nov;78(11):6840-4
references.pmid: 6947258
references.citation: J Exp Biol. 1988 Sep;139:51-65
references.pmid: 2850339
references.citation: J R Soc Interface. 2012 Jan 7;9(66):170-82
references.pmid: 21676968
references.citation: Mol Endocrinol. 2013 Apr;27(4):606-18
references.pmid: 23393127
references.citation: Science. 1980 Mar 21;207(4437):1371-3
references.pmid: 6766566
references.citation: Front Neuroendocrinol. 2010 Jul;31(3):322-40
references.pmid: 20451543
references.citation: Am J Physiol. 1984 Oct;247(4 Pt 1):E564-8
references.pmid: 6496673
references.citation: Cell. 2013 Feb 28;152(5):945-56
references.pmid: 23452846
references.citation: Nature. 1998 Apr 30;392(6679):933-6
references.pmid: 9582075
references.citation: Sci Signal. 2012 Feb 28;5(213):ra17
references.pmid: 22375055
references.citation: Diabetes. 2012 Sep;61(9):2269-79
references.pmid: 22688333
references.citation: Endocrinology. 1995 Apr;136(4):1603-9
references.pmid: 7895670
references.citation: Mol Cell Endocrinol. 2001 Oct 25;183(1-2):29-32
references.pmid: 11604221
references.citation: Physiol Rev. 2001 Jul;81(3):1269-304
references.pmid: 11427696
references.citation: Nat Rev Neurosci. 2010 Oct;11(10):710-8
references.pmid: 20842176
references.citation: J Biol Chem. 2010 Jun 25;285(26):20262-72
references.pmid: 20406815
references.citation: Endocrinology. 1989 Aug;125(2):917-24
references.pmid: 2502379
references.citation: Endocrinology. 1981 Aug;109(2):376-85
references.pmid: 6788538
references.citation: PLoS One. 2009 Sep 29;4(9):e7244
references.pmid: 19787048
references.citation: Am J Obstet Gynecol. 1991 Nov;165(5 Pt 1):1515-23
references.pmid: 1957888