Gonadotrophin‐Releasing Hormone Signalling Downstream of Calmodulin

Abstract

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 Ca2+ levels, which is a result of both calcium influx and mobilisation from intracellular stores. However, Ca2+ 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 β‐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 gonadotrophs, 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.

The genetic basis for ecological adaptation of the Atlantic herring revealed by genome sequencing

“…Interestingly, our strongest signals (p<1x10 -120 ) in this contrast is located within and up to 25 kb upstream of TSHR encoding thyroid-stimulating hormone receptor, which has a central role in this pathway in birds and mammals ( Nakao et al, 2008 ; Ono et al, 2008 ; Hanon et al, 2008 ). Further, a second gene in the same scaffold (190/1420), calmodulin has a role in initiating reproduction following secretion of gonadotropin-releasing hormone (GnRH) ( Melamed et al, 2012 ) downstream of TSHR signalling in photoperiodic regulation of reproduction. SOX11 , one of the genes in the associated region in scaffold 1440 ( Figure 4C ), encodes a transcription factor that controls GnRH expression in GnRH-secreting neurons ( Kim et al, 2011 ).…”

Hormone-related pathways and risk of breast cancer subtypes in African American women

“…CALM2 maps to chromosome 2p21 and is one of three genes that encode the protein calmodulin (CaM). CALM2 was included in the present study because of CaM's involvement in gonadotropin-releasing hormone (GnRH) signaling: GnRH induces calcium influx, which activates CaM leading to a variety of downstream effects that result in gonadotropin gene expression [65]. Thus, CALM2 may impact breast cancer susceptibility through its effects on hormone synthesis.…”

Gonadotropin gene transcription is activated by menin-mediated effects on the chromatin

“…The mechanisms through which these genes are activated in basal conditions and via induction of various signaling cascades and genespecific transcription factors have been described in some detail [1][2][3][4][5][6]. However, in order for these proteins to bind the gene promoters and transcription to be activated, the DNA must be made accessible through altering the structure of the chromatin.…”