Gonadotrophin-releasing hormone receptors C
Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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GnRH1 and GnRH2 receptors (provisonal nomenclature [13], also called Type I and Type II GnRH receptor, respectively [30]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [29-30,37]. GnRH I (GNRH1, P01148) (p-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is a hypothalamic decapeptide also known as luteinizing hormone-releasing hormone, gonadoliberin, luliberin, gonadorelin or simply as GnRH. It is a member of a family of similar peptides found in many species [29-30,37] including GnRH II (GNRH2, O43555) (pGlu-His-Trp-Ser-His-Gly-Trp-Tyr-Pro-Gly-NH2 (which is also known as chicken GnRH-II). Receptors for three forms of GnRH exist in some species but only GnRH I and GnRH II and their cognate receptors have been found in mammals [29-30,37]. GnRH1 receptors are expressed by pituitary gonadotrophs, where they mediate the effects of GnRH on gonadotropin hormone synthesis and secretion that underpin central control of mammalian reproduction. GnRH analogues are used in assisted reproduction and to treat steroid hormone-dependent conditions [18]. Notably, agonists cause desensitization of GnRH-stimulated gonadotropin secretion and the consequent reduction in circulating sex steroids is exploited to treat hormone-dependent cancers of the breast, ovary and prostate [18]. GnRH1 receptors are selectively activated by GnRH I and all lack the COOH-terminal tails found in other GPCRs. GnRH2 receptors do have COOH-terminal tails and (where tested) are selective for GnRH II over GnRH I. GnRH2 receptors are expressed by some primates but not by humans [31]. Phylogenetic classifications divide GnRH receptors into three [30] or five groups [41] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene. The structure of the GnRH1 receptor in complex with elagolix has been elucidated [42].
Receptors
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GnRH1 receptor
C
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GnRH2 receptor
C
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Concise Guide to PHARMACOLOGY citation:
Alexander SP, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL et al. (2021) THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors. Br J Pharmacol. 176 Suppl 1:S27-S156.
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GnRH1 and GnRH2 receptors couple primarily to Gq/11 [14] but coupling to Gs and Gi is evident in some systems [20-21]. GnRH2 receptors may also mediate (heterotrimeric) G protein-independent signalling to protein kinases [4]. There is increasing evidence for expression of GnRH receptors on hormone-dependent cancer cells where they can exert antiproliferative and/or proapoptotic effects and mediate effects of cytotoxins conjugated to GnRH analogues [7,16,24,36]. In some human cancer cell models GnRH II (GNRH2, O43555) is more potent than GnRH I (GNRH1, P01148), implying mediation by GnRH2 receptors [15], but GnRH2 receptors are not expressed by humans because the human GNRHR2 gene contains a frame shift and internal stop codon [31]. The possibility remains that this gene generates GnRH2 receptor-related proteins (other than the full-length receptor) that mediate responses to GnRH II (GNRH2, O43555) (see [34]). Alternatively, evidence for multiple active GnRH receptor conformations [4-5,10,27,30] raises the possibility that GnRH1 receptor-mediated proliferation inhibition in hormone-dependent cancer cells is dependent upon a conformation that couples to Gi rather than Gq/11 proteins as in pituitary cells [5,27]. Loss-of-function mutations in the GnRH1 receptor and deficiency of GnRH I (GNRH1, P01148) are associated with hypogonadotropic hypogonadism although some 'loss of function' mutations may actually prevent trafficking of 'functional' GnRH1 receptors to the cell surface, as evidenced by recovery of function by nonpeptide antagonists [23]. Human GnRH1 receptors are poorly expressed at the cell surface because of failure to meet structural quality control criteria for endoplasmic reticulum exit [11,23], and this increases susceptibility to point mutations that further impair trafficking [11,23]. GnRH receptor signalling may require receptor oligomerisation [8,19].