Information transfer in gonadotropin-releasing hormone (GnRH) signaling: extracellular signal-regulated kinase (ERK)-mediated feedback loops control hormone sensing

Kathryn L Garner, Rebecca M Perrett, Margaritis Voliotis, Clive Bowsher, George R Pope, Thanh Pham, Christopher J Caunt, Krasimira Tsaneva-Atanasova, Craig A McArdle

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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.

LanguageEnglish
Pages2246-2259
Number of pages14
JournalJournal of Biological Chemistry
Volume291
Issue number5
Early online date7 Dec 2015
DOIs
StatusPublished - 29 Jan 2016

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Extracellular Signal-Regulated MAP Kinases
Gonadotropin-Releasing Hormone
Hormones
Feedback
Cell signaling
LHRH Receptors
Dual-Specificity Phosphatases
Communication channels (information theory)
NFATC Transcription Factors
Information Theory
Information theory
Chemical activation
Sensors
Proteins
Experiments

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Information transfer in gonadotropin-releasing hormone (GnRH) signaling : extracellular signal-regulated kinase (ERK)-mediated feedback loops control hormone sensing. / Garner, Kathryn L; Perrett, Rebecca M; Voliotis, Margaritis; Bowsher, Clive; Pope, George R; Pham, Thanh; Caunt, Christopher J; Tsaneva-Atanasova, Krasimira; McArdle, Craig A.

In: Journal of Biological Chemistry, Vol. 291, No. 5, 29.01.2016, p. 2246-2259.

Research output: Contribution to journalArticle

Garner, KL, Perrett, RM, Voliotis, M, Bowsher, C, Pope, GR, Pham, T, Caunt, CJ, Tsaneva-Atanasova, K & McArdle, CA 2016, 'Information transfer in gonadotropin-releasing hormone (GnRH) signaling: extracellular signal-regulated kinase (ERK)-mediated feedback loops control hormone sensing' Journal of Biological Chemistry, vol. 291, no. 5, pp. 2246-2259. DOI: 10.1074/jbc.M115.686964
Garner, Kathryn L ; Perrett, Rebecca M ; Voliotis, Margaritis ; Bowsher, Clive ; Pope, George R ; Pham, Thanh ; Caunt, Christopher J ; Tsaneva-Atanasova, Krasimira ; McArdle, Craig A. / Information transfer in gonadotropin-releasing hormone (GnRH) signaling : extracellular signal-regulated kinase (ERK)-mediated feedback loops control hormone sensing. In: Journal of Biological Chemistry. 2016 ; Vol. 291, No. 5. pp. 2246-2259
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