Journal of Neuroendocrinology, 2012, 24, 1463–1475 REVIEW ARTICLE © 2012 The Authors. Journal of Neuroendocrinology © 2012 British Society for Neuroendocrinology Gonadotrophin-Releasing Hormone Signalling Downstream of Calmodulin P. Melamed*†, D. Savulescu*, S. Lim†, A. Wijeweera*, Z. Luo† 1 , M. Luo† 2 and L. Pnueli* *Faculty of Biology, Technion-Israel Institute of Technology, Haifa, Israel. †Department of Biological Sciences, National University of Singapore, Singapore, Singapore. Journal of Neuroendocrinology Correspondence to: P. Melamed, Faculty of Biology, Technion-Israel Institute of Technology, Haifa 32000, Israel (e-mail: philippa.melamed@gmail. com). 1 Present address: Stowers Institute for Medical Research, Kansas City MO, USA. 2 Present address: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston TX, USA Gonadotrophin-releasing hormone (GnRH) regulates reproduction via binding a G-protein coupled receptor on the surface of the gonadotroph, through which it transmits signals, mostly via the mitogen-activated protein (MAPK) cascade, to increase synthesis of the gonadotrophin hormones: luteinising hormone (LH) and follicle-stimulating hormone (FSH). Activation of the MAPK cascade requires an elevation in cytosolic Ca 2+ levels, which is a result of both calcium influx and mobilisation from intracellular stores. However, Ca 2+ also transmits signals via an MAPK-independent pathway, through binding calmodulin (CaM), which is then able to bind a number of proteins to impart diverse downstream effects. Although the ability of GnRH to activate CaM was recognised over 20 years ago, only recently have some of the downstream effects been elucidated. GnRH was shown to activate the CaM-dependent phosphatase, calcineurin, which targets gonadotrophin gene expression both directly and indirectly via transcription factors such as nuclear factor of activated T-cells and Nur77, the Transducer of Regulated CREB (TORC) co-activators and also the prolyl isomerase, Pin1. Gonadotrophin gene expression is also regulated by GnRH-induced CaM-dependent kinases (CaMKs); CaMKI is able to derepress the histone deacetylase-inhibition of b-subunit gene expression, whereas CaMKII appears to be essential for the GnRH-activation of all three subunit genes. Asides from activating gonadotrophin gene expression, GnRH also exerts additional effects on gonadotroph function, some of which clearly occur via CaM, including the proliferation of immature gonado- trophs, which is dependent on calcineurin. In this review, we summarise these pathways, and discuss the additional functions that have been proposed for CaM with respect to modifying GnRH-induced signalling pathways via the regulation of the small GTP-binding protein, Gem, and/or the regulator of G-protein signalling protein 2. Key words: GnRH, gonadotrophin, gonadotroph, calmodulin, calcineurin, CaMK doi: 10.1111/j.1365-2826.2012.02359.x Gonadotrophin-releasing hormone (GnRH), the gonadotroph and calmodulin Reproduction is regulated through a complex interplay of hormones and feedback operating along the hypothalamic-pituitary-gonadal axis, of which the hypothalamic hormone, gonadotrophin-releasing hormone (GnRH), is the predominant activator. GnRH binds a membrane-bound receptor (GnRHR) on the pituitary gonadotrophs to stimulate transcription of the three gonadotrophin genes: the common a subunit (aGSU) and the hormone specific b-subunits [luteinising hormone (LH)b and follicle-stimulating hormone (FSH)b] (Fig. 1), as well as stimulating the secretion of LH. As part of its regulation of gonadotroph activity and function, GnRH also affects these cells in numerous other ways, including cell proliferation and apoptosis, cell shape and mobility, as well as their responsiveness to other hormones (1–6). The GnRH arrives at the pituitary in pulses whose amplitude and frequency vary with ensuing sexual maturity and during the oestrous cycle; these distinct pulse frequencies direct the preferen- tial expression of either LHb or FSHb (7–10). Subsequent to their synthesis, the gonadotrophic hormones, LH and FSH, are secreted into the circulation from where they regulate gonadal activity. The pivotal role of GnRH in functioning of the gonadotrophs and the regulation of reproduction is seen at puberty, when GnRH delivery to the gonadotroph is the only endogenous block to the reawaken- ing of the pituitary-gonadal axis and reproductive potential (11).