Pulsatile hormonal signaling to extracellular signal-regulated kinase: exploring system sensitivity to gonadotropin-releasing hormone pulse frequency and width.
Gonadotropin-releasing hormone (GnRH) is secreted in brief pulses that stimulate synthesis and secretion of pituitary gonadotropin hormones and thereby mediate control of reproduction. It acts via G-protein-coupled receptors to stimulate effectors, including ERK. Information could be encoded in GnRH pulse frequency, width, amplitude, or other features of pulse shape, but the relative importance of these features is unknown. Here we examine this using automated fluorescence microscopy and mathematical modeling, focusing on ERK signaling. The simplest scenario is one in which the system is linear, and response dynamics are relatively fast (compared with the signal dynamics). In this case integrated system output (ERK activation or ERK-driven transcription) will be roughly proportional to integrated input, but we find that this is not the case. Notably, we find that relatively slow response kinetics lead to ERK activity beyond the GnRH pulse, and this reduces sensitivity to pulse width. More generally, we show that the slowing of response kinetics through the signaling cascade creates a system that is robust to pulse width. We, therefore, show how various levels of response kinetics synergize to dictate system sensitivity to different features of pulsatile hormone input. We reveal the mathematical and biochemical basis of a dynamic GnRH signaling system that is robust to changes in pulse amplitude and width but is sensitive to changes in receptor occupancy and frequency, precisely the features that are tightly regulated and exploited to exert physiological control in vivo.
From the Laboratories for Integrative Neuroscience and Endocrinology, School of Clinical Sciences, University of Bristol, Bristol BS1 3NY, United Kingdom.
Rebecca M
RM
Perrett
Margaritis
M
Voliotis
Stephen P
SP
Armstrong
Robert C
RC
Fowkes
George R
GR
Pope
Krasimira
K
Tsaneva-Atanasova
Craig A
CA
McArdle
D021581:Active Transport, Cell Nucleus; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005786:Gene Expression Regulation; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006728:Hormones / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008156:Luciferases / Q000378:metabolism; D008962:Models, Theoretical; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D059467:Transcriptome
D006728:Hormones; D049452:Green Fluorescent Proteins; D007987:Gonadotropin-Releasing Hormone; D008156:Luciferases; D048049:Extracellular Signal-Regulated MAP Kinases
Cell Signaling; ERK; GnRH; MAP Kinases (MAPKs); Mathematical Modeling; Receptors