Module Dynamics of the GnRH Signal Transduction Network

Krakauer, David C.; Page, Karen M.; Sealfon, Stuart C.

doi:10.1006/jtbi.2002.3092

Cited by 21 publications

(42 citation statements)

References 41 publications

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“…The function F could be thought of as a rapid equilibrium approximation to fast signaling dynamics that occur prior to the production of b . A similar model was shown to respond to increases in mean input dose in a study of GnRH receptor induced signaling pathways (Model 1 in [16]). The steady state level of b in response to a constant input γ(t) = A is simply F(A) .…”

Section: Resultsmentioning

confidence: 99%

“…Thus, the results demonstrated in this study may help in understanding responses in feed-forward signaling pathways triggered by GnRH. While there have been many detailed experimental (for review, see [20], [21]) and theoretical (for instance, [16], [22], [25]) studies of the GnRH receptor-induced signaling network, it remains to be determined precisely which components are responsible for the bell-shaped frequency responses of LH and FSH production in pituitary gonadotrophs.…”

Section: Discussionmentioning

confidence: 99%

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Interpreting Frequency Responses to Dose-Conserved Pulsatile Input Signals in Simple Cell Signaling Motifs

et al. 2014

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Interpreting Frequency Responses to Dose-Conserved Pulsatile Input Signals in Simple Cell Signaling Motifs

et al. 2014

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“…The GnRH signaling system is unusual in being largely temporally encoded. GnRH is released by the brain in short roughly hourly pulses, and the pulse frequency is important in determining the biosynthetic responses (4,5,(55)(56)(57). Frequency encoding requires the gonadotrope to process each individual pulse.…”

Section: Discussionmentioning

confidence: 99%

Mixed Analog/Digital Gonadotrope Biosynthetic Response to Gonadotropin-releasing Hormone

Ruf

Park

Hayot

et al. 2006

Journal of Biological Chemistry

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Mammalian reproduction requires gonadotropin-releasing hormone (GnRH)-mediated signaling from brain neurons to pituitary gonadotropes. Because the pulses of released GnRH vary greatly in amplitude, we studied the biosynthetic response of the gonadotrope to varying GnRH concentrations, focusing on extracellular-regulated kinase (ERK) phosphorylation and egr1 mRNA and protein production. The overall average level of ERK activation in populations of cells increased non-cooperatively with increasing GnRH and did not show evidence of either ultrasensitivity or bistability. However, automated image analysis of single-cell responses showed that whereas individual gonadotropes exhibited two response states, inactive and active, both the probability of activation and the average response in activated cells increased with increasing GnRH concentration. These data indicate a hybrid single-cell response having both digital (switch-like) and analog (graded) features. Mathematical modeling suggests that the hybrid response can be explained by indirect thresholding of ERK activation resulting from the distributed structure of the GnRH-modulated network. The hybrid response mechanism improves the reliability of noisy reproductive signal transmission from the brain to the pituitary.Mammalian reproduction and the survival of a species rely on a precise orchestration of temporally and spatially distributed molecular events. The control of reproduction represents a difficult engineering problem, because noisy molecular processes within cells that occur on time scales of minutes must regulate brain, pituitary, and gonadal activity in a process with an overall periodicity of days to weeks, depending on the species. At the center of this coordinated reproductive activity lies the pituitary gonadotrope, which converts hormone signals secreted by the brain into the biosynthesis and secretion of pituitary hormones controlling gonadal responses.The hypothalamus secretes discrete pulses of gonadotropinreleasing hormone (GnRH) 2 (for a review, see Refs. 1-3). GnRH interacts with high affinity GnRH receptors on the gonadotrope membrane to modulate the biosynthesis and release of the gonadotropins luteinizing hormone and follicle-stimulating hormone (4 -6). The function of the reproductive axis depends on appropriate responses of the gonadotrope to GnRH despite the high interpulse variability in the amplitude of GnRH secreted by the brain (3,(7)(8)(9)(10)(11)(12). Elucidating the mechanisms underlying the response of the gonadotrope to varying concentrations of GnRH is important for understanding the design principles of this key response locus for mammalian physiology.GnRH directs two distinguishable gonadotrope activities, the biosynthesis of gonadotropins and their secretion. We focus here on the biosynthetic response. The GnRH receptor is a heptahelical G protein-coupled receptor that modulates a signaling network leading to activation of protein kinases and regulation of both transcription and translation (13). The gene network responses...

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“…Saturation nonlinearities for the production of adenyl cyclase and cAMP have been considered in other contexts [12]. Delays have been previously modelled, but for the Ca 2+ pathway alone [13, 14]. …”

Section: Resultsmentioning

confidence: 99%

A Two-Pathway Mathematical Model of the LH Response to GnRH that Predicts Self-Priming

Evans

Wilkinson

Wall

2013

International Journal of Endocrinology

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An acute response of LH to a stimulatory pulse of GnRH is modelled as a result of a pathway (Pathway I) that consists of two compartments including a single (rate limiting) intermediate. In addition, a second pathway (Pathway II) was added, consisting of an intermediate transcription factor and subsequently a synthesised protein. Pathway II had a delayed effect on LH release due to the time taken to produce the intermediate protein. The model included synergism between these two pathways, which yielded an augmented response. The model accounts for a number of observations, including GnRH self-priming and the biphasic pattern of LH response. The same model was used to fit the data of the LH response when gonadotrophs responded to the addition of oxytocin in the response with a shoulder on the profile. Pathway I is able to be conceptualised as the basic Ca2+-mediated pathway. Pathway II contains features characteristic of the cAMP-mediated pathway. Thus, we have provided an explanation for details of the nature of the profile of LH secretion and additionally enabled incorporation of cAMP in an integrating model. The study investigated the possibility of two interacting pathways being at the basis of both the shoulder on the LH surges and self-priming, and the model illustrates that this appears to be highly likely.

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Module Dynamics of the GnRH Signal Transduction Network

Cited by 21 publications

References 41 publications

Interpreting Frequency Responses to Dose-Conserved Pulsatile Input Signals in Simple Cell Signaling Motifs

Interpreting Frequency Responses to Dose-Conserved Pulsatile Input Signals in Simple Cell Signaling Motifs

Mixed Analog/Digital Gonadotrope Biosynthetic Response to Gonadotropin-releasing Hormone

A Two-Pathway Mathematical Model of the LH Response to GnRH that Predicts Self-Priming

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