title: Information Transfer in Gonadotropin-releasing Hormone (GnRH) Signaling: EXTRACELLULAR SIGNAL-REGULATED KINASE (ERK)-MEDIATED FEEDBACK LOOPS CONTROL HORMONE SENSING.
abstract: Cell signaling pathways are noisy communication channels, and statistical measures derived from information theory can be used to quantify the information they transfer. Here we use single cell signaling measures to calculate mutual information as a measure of information transfer via gonadotropin-releasing hormone (GnRH) receptors (GnRHR) to extracellular signal-regulated kinase (ERK) or nuclear factor of activated T-cells (NFAT). This revealed mutual information values <1 bit, implying that individual GnRH-responsive cells cannot unambiguously differentiate even two equally probable input concentrations. Addressing possible mechanisms for mitigation of information loss, we focused on the ERK pathway and developed a stochastic activation model incorporating negative feedback and constitutive activity. Model simulations revealed interplay between fast (min) and slow (min-h) negative feedback loops with maximal information transfer at intermediate feedback levels. Consistent with this, experiments revealed that reducing negative feedback (by expressing catalytically inactive ERK2) and increasing negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced information transfer from GnRHR to ERK. It was also reduced by blocking protein synthesis (to prevent GnRH from increasing DUSP expression) but did not differ for different GnRHRs that do or do not undergo rapid homologous desensitization. Thus, the first statistical measures of information transfer via these receptors reveals that individual cells are unreliable sensors of GnRH concentration and that this reliability is maximal at intermediate levels of ERK-mediated negative feedback but is not influenced by receptor desensitization.
authors.affiliation: From the Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Garner
authors.affiliation: From the Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Perrett
authors.affiliation: School of Mathematics, University of Bristol, Bristol, BS8 1TW, United Kingdom.
authors.forename: Margaritis
authors.initials: M
authors.lastname: Voliotis
authors.affiliation: School of Mathematics, University of Bristol, Bristol, BS8 1TW, United Kingdom.
authors.forename: Clive
authors.initials: C
authors.lastname: Bowsher
authors.affiliation: From the Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom.
authors.forename: George R
authors.initials: GR
authors.lastname: Pope
authors.affiliation: Texas A and M University Corpus Christi, Corpus Christi, Texas 78412.
authors.forename: Thanh
authors.initials: T
authors.lastname: Pham
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, United Kingdom, and.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Caunt
authors.affiliation: Department of Mathematics, College of Engineering, Mathematics, and Physical Sciences, University of Exeter, Exeter, EX4 4QF, United Kingdom.
authors.forename: Krasimira
authors.initials: K
authors.lastname: Tsaneva-Atanasova
authors.affiliation: From the Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol, BS1 3NY, United Kingdom, craig.mcardle@bristol.ac.uk.
authors.forename: Craig A
authors.initials: CA
authors.lastname: McArdle
mesh_terms: D002384:Catalysis; D003198:Computer Simulation; D003513:Cycloheximide / Q000737:chemistry; D054637:Dual-Specificity Phosphatases / Q000378:metabolism; D025461:Feedback, Physiological; D015971:Gene Expression Regulation, Enzymologic; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D008962:Models, Theoretical; D050778:NFATC Transcription Factors / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000737:chemistry; D011966:Receptors, LHRH / Q000378:metabolism*; D015398:Signal Transduction; D013269:Stochastic Processes
chemical_list: D050778:NFATC Transcription Factors; D011500:Protein Synthesis Inhibitors; D011966:Receptors, LHRH; D007987:Gonadotropin-Releasing Hormone; D003513:Cycloheximide; D048052:Mitogen-Activated Protein Kinase 3; C442320:DUSP5 protein, human; D054637:Dual-Specificity Phosphatases
keywords: G protein-coupled receptor (GPCR); cell signaling; extracellular signal-regulated kinase (ERK); gonadotropin-releasing hormone; mathematical modeling; mitogen-activated protein kinase (MAPK); mutual information; signal transduction