Module Dynamics of GnRH Signal Transduction Networks

We analyze computational modules of a frequency-decoding signal transduction network. The gonadotropin releasing hormone (GnRH) signal transduction network mediates the biosynthesis and release of the gonadotropins, luteinizing hormone (LH) and follicle stimulating hormone (FSH). The pulsatile pattern of GnRH production by the hypothalamus has a critical influence on the release and synthesis of gonadotropins in the pituitary. In humans, slower pulses lead to the expression of the $\beta$ subunit of the LH protein and cause anovulation and amenorrhea. Higher frequency pulses lead to expression of alpha subunit and a hypogonadal state. The frequency sensitivity is a consequence of the structure of the GnRH signal transduction network. We analyze individual components of this network, organized into three network architectures, and describe the frequency-decoding capabilities of each of these modules. We find that these modules are comparable to simple circuit elements, some of which integrate and others which perform as frequency sensitive filters. We propose that the cell computes by exploiting variation in the time scales of gene activation (phosphorylation) and gene expression.