Pulsatile Hormonal Signaling to Extracellular Signal-Regulated Kinase: Exploring System Sensitivity to Gonadotropin-Releasing Hormone Pulse Frequency and Width. [Cell Biology]

January 30th, 2014 by Perrett, R. M., Voliotis, M., Armstrong, S. P., Fowkes, R. C., Pope, G. R., Tsaneva-Atanasova, K., McArdle, C. A.

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 to 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.
  • Posted in Journal of Biological Chemistry, Publications
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