Endocrine Abstracts (2015) 38 P359 | DOI: 10.1530/endoabs.38.P359

Information transfer in GnRH signalling: ERK-mediated feedback loops control hormone sensing

Kathryn Garner1, Rebecca Perrett1, Margaritis Voliotis2, Thanh Pham3, Krasimira Tsaneva-Atanasova4 & Craig McArdle1

1School of Clinical Sciences, University of Bristol, Bristol, UK; 2School of Mathematics, University of Bristol, Bristol, UK; 3Texas A&M University, College Station, Texas, USA; 4Department of Mathematics, University of Exeter, Exeter, UK.

Single cell measurements of signalling proteins typically reveal high cell–cell variability raising questions about how reliably individual cells sense their environment in order to make decisions. Information theoretic approaches can be used to explore such sensing, treating cell signalling pathways as ‘noisy’ communication channels. Mutual information (MI) can be calculated between system inputs and outputs as a statistical measure of the reliability of sensing (Voliotis et al. PNAS 111 E326, 2014). GnRH acts via Gq/11-coupled seven-transmembrane receptors to stimulate ERK, but information transfer has not previously been quantified for these (or other) hormone receptors. Here we do so using automated fluorescence microscopy to quantify dual-phosphorylated (pp)ERK in HeLa cells transduced with recombinant adenovirus to express the GnRH receptor. Population-averaged data showed concentration-dependent responses to GnRH that were rapid (maximal at 5 min) and transient (near basal at 60–360 min). Individual cell measures were used to calculate MI, which showed a similar time course for information transfer; I(ppERK;GnRH) increased to >0.6 bits at 5 min with a gradual reduction to <0.2 bits by 60–360 min. We found that MI is controlled by the relative strength of distinct feedback loops. Reducing fast negative feedback (by expressing catalytically inactive ERK2 alongside siRNA to knock down endogenous ERK1/2) and increasing slow negative feedback (by Egr1-driven expression of dual-specificity phosphatase 5 (DUSP5)) both reduced MI between GnRH concentrations and ppERK responses. Information transfer was also reduced when protein synthesis was blocked to prevent GnRH from increasing DUSP expression. MI values were always <1, implying that information transfer through these pathways is insufficient for an individual cell to unambiguously distinguish between two states of its environment. Thus, by quantifying information transfer we find that individual cells are unreliable sensors of GnRH concentration and that this is influenced by fast and slow ERK-mediated negative feedback.

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