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Gonadotrophin‐Releasing Hormone Signalling Downstream of Calmodulin
Author(s) -
Melamed P.,
Savulescu D.,
Lim S.,
Wijeweera A.,
Luo Z.,
Luo M.,
Pnueli L.
Publication year - 2012
Publication title -
journal of neuroendocrinology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.062
H-Index - 116
eISSN - 1365-2826
pISSN - 0953-8194
DOI - 10.1111/j.1365-2826.2012.02359.x
Subject(s) - medicine , endocrinology , creb , calcineurin , microbiology and biotechnology , protein kinase a , gonadotropic cell , signal transduction , calmodulin , biology , gq alpha subunit , mapk/erk pathway , camk , transcription factor , chemistry , kinase , luteinizing hormone , hormone , g protein , gene , biochemistry , calcium , autophosphorylation , transplantation
Gonadotrophin‐releasing hormone ( G n RH ) 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 ( C a M ), which is then able to bind a number of proteins to impart diverse downstream effects. Although the ability of G n RH to activate C a M was recognised over 20 years ago, only recently have some of the downstream effects been elucidated. G n RH was shown to activate the C a M ‐dependent phosphatase, calcineurin, which targets gonadotrophin gene expression both directly and indirectly via transcription factors such as nuclear factor of activated T‐cells and N ur77, the Transducer of Regulated CREB (TORC) co‐activators and also the prolyl isomerase, P in1. Gonadotrophin gene expression is also regulated by G n RH ‐induced C a M ‐dependent kinases ( C a MK s); C a MKI is able to derepress the histone deacetylase ‐inhibition of β‐subunit gene expression, whereas CaMKII appears to be essential for the G n RH ‐activation of all three subunit genes. Asides from activating gonadotrophin gene expression, G n RH also exerts additional effects on gonadotroph function, some of which clearly occur via C a M , 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 C a M with respect to modifying G n RH ‐induced signalling pathways via the regulation of the small GTP ‐binding protein, G em, and/or the r egulator of G ‐protein signalling protein 2.