Pulsatile Hormonal Signaling to Extracellular Signal-Regulated Kinase: Exploring System Sensitivity to Gonadotropin-Releasing Hormone Pulse Frequency and Width
Perrett, Rebecca M.
Armstrong, Stephen P.
Fowkes, Robert C.
Pope, George R.
McArdle, Craig A.
Journal of Biological Chemistry
American Society for Biochemistry and Molecular Biology
This is an open access article made available under a Creative Commons Attribution Unported License: http://creativecommons.org/licenses/by/3.0/
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.
Medical Research Council
Biochemical and Biophysical Science Research Council
Open access article
© 2014 by The American Society for Biochemistry and Molecular Biology, Inc. This research was originally published in Journal of Biological Chemistry. Rebecca M. Perrett, Margaritis Voliotis, Stephen P. Armstrong, Robert C. Fowkes, George R. Pope, Krasimira Tsaneva-Atanasova and Craig A. McArdle. Pulsatile Hormonal Signaling to Extracellular Signal-Regulated Kinase - Exploring System Sensitivity to Gonadotropin-Releasing Hormone Pulse Frequency and Width. Journal of Biological Chemistry.2014. Vol. 28: 7873-7883.
Vol. 289 (11), pp. 7873 - 7883