Information Transfer in Gonadotropin-releasing Hormone (GnRH) Signaling

Garner, Kathryn, Perrett, Rebecca M., Voliotis, Margaritis, Bowsher, Clive, Pope, George R., Pham, Thanh, Caunt, Christopher J., Tsaneva-Atanasova, Krasimira and McArdle, Craig A. (2015) Information Transfer in Gonadotropin-releasing Hormone (GnRH) Signaling. The Journal of Biological Chemistry, 291 (5). pp. 2246-2259. ISSN 0021-9258

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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.

Item Type: Article
Uncontrolled Keywords: Cell signaling, extracellular signal-regulated kinase (ERK), G protein-coupled receptor (GPCR), mathematical modeling, mitogen-activated protein kinase (MAPK), gonadotropin-releasing hormone, mutual information, signal transduction
Subjects: C700 Molecular Biology, Biophysics and Biochemistry
Department: Faculties > Health and Life Sciences > Applied Sciences
Depositing User: John Coen
Date Deposited: 03 Jun 2020 13:59
Last Modified: 31 Jul 2021 17:35

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