Abstract
Gonadotropin-releasing hormone (GnRH) is the primary regulator of mammalian reproductive function in both males and females. It acts via G-protein coupled receptors on gonadotropes to stimulate synthesis and secretion of the gonadotropin hormones luteinizing hormone and follicle-stimulating hormone. These receptors couple primarily via G-proteins of the Gq/ll family, driving activation of phospholipases C and mediating GnRH effects on gonadotropin synthesis and secretion. There is also good evidence that GnRH causes activation of other heterotrimeric G-proteins (Gs and Gi) with consequent effects on cyclic AMP production, as well as for effects on the soluble and particulate guanylyl cyclases that generate cGMP. Here we provide an overview of these pathways. We emphasize mechanisms underpinning pulsatile hormone signaling and the possible interplay of GnRH and autocrine or paracrine regulatory mechanisms in control of cyclic nucleotide signaling.
Highlights
This differs from earlier models [109, 163, 165, 184,185,186] in that it incorporates Ca2+/calmodulin/calcineurin/nuclear factor of activated T-cells (NFAT) and Raf/MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) modules, includes cellular compartmentalization and importantly, lacks upstream negative feedback. This model accurately predicts wet-lab data for activation and nuclear translocation of ERK2-green fluorescent protein (GFP) and NFAT-emerald fluorescent protein (EFP) as validated by modeling responses to Gonadotropin-releasing hormone (GnRH) pulses at a range of concentrations and frequencies, and these two could be used as inputs to the transcriptome. Using this model we considered the possibility that two transcription factors (TF1 and TF2) act at distinct sites on a common gene promoter named gonadotropin subunit (GSU), a generic term used because this is likely the case for the α-gonadotropin subunit (αGSU), LHβ, and FSHβ gonadotropin subunit genes, as it is for many other ERK and NFAT target genes [178,179,180,181,182,183]
Type I mammalian GnRH receptor (GnRHR) of pituitary gonadotropes signal primarily via Gq/11. They have no C-terminal tail and do not elicit the C-tail dependent and heterotrimeric G-protein independent signaling seen with many other G-protein coupled receptor (GPCR). These features could ensure that the type I mammalian GnRHR of pituitary gonadotropes faithfully transduce the portal blood GnRH signal into phospholipase C (PLC) activation in the target cells, and this could arguably confer selective advantage by
pituitary adenylyl cyclase activating polypeptide (PACAP) has pronounced effects on cyclic adenosine monophosphate (cAMP) production in gonadotropes and gonadotropederived cell lines, and the possibility exists that the modest stimulatory effects of GnRH pale into insignificance in gonadotropes exposed to PACAP
Summary
In common with many other GPCRs, GnRHRs of gonadotropes and gonadotrope-lineage cells act primarily via Gαq/11 to activate phospholipase C (PLC), elevating cytoplasmic [Ca2+] and activating protein kinase C (PKC) isozymes, both of which are important for GnRHR-mediated effects on gonadotropin synthesis and secretion (Figure 1) [2,3,4,5,6, 29, 31, 41,42,43,44,45,46]. Gonadotropin-releasing hormone effects on gonadotropin synthesis are largely mediated through stimulation of MAPK cascades, the ERK pathway (Figure 1) [85], which is PKC dependent in αT3-1 and LβT2 gonadotrope-derived cells [79].
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