scholarly journals Type II gonadotrophin-releasing hormone (GnRH-II) in reproductive biology

Reproduction ◽  
2003 ◽  
pp. 271-278 ◽  
Author(s):  
AJ Pawson ◽  
K Morgan ◽  
SR Maudsley ◽  
RP Millar
Keyword(s):  
Receptor Gene ◽  
Gnrh Receptor ◽  
Specific Gene ◽  
Type I ◽  
Type Ii ◽  
Releasing Hormone ◽  
Human Type ◽  
Gnrh Receptors ◽  
Gonadotrophin Releasing Hormone ◽  
Ligand Precursors

Humans may be particularly unusual with respect to the gonadotrophin-releasing hormone (GnRH) control of their reproductive axis in that they possess two distinct GnRH precursor genes, on chromosomes 8p11-p21 and 20p13, but only one conventional GnRH receptor subtype (type I GnRH receptor) encoded within the genome, on chromosome 4. A disrupted human type II GnRH receptor gene homologue is present on chromosome 1q12. The genes encoding GnRH ligand precursors and GnRH receptors have now been characterized in a broad range of vertebrate species, including fish, amphibians and mammals. Ligand precursors and receptors can be categorized into three phylogenetic families. Members of each family exist in primitive vertebrates, whereas mammals exhibit selective loss of ligand precursor and receptor genes. One interpretation of these findings is that each ligand-cognate receptor family may have evolved to fulfil a separate function in reproductive physiology and that species-specific gene inactivation, modification or loss may have occurred during evolution when particular roles have become obsolete or subject to regulation by a different biochemical pathway. Evidence in support of this concept is available following the characterization of the chromosomal loci encoding the human type II GnRH receptor homologue, a rat type II GnRH receptor gene remnant (on rat chromosome 18) and a mouse type II GnRH ligand precursor gene remnant (on mouse chromosome 2). Whether type I GnRH and type II GnRH peptides elicit different signalling responses in humans by activation of the type I GnRH receptor in a cell type-specific fashion remains to be shown. Recent structure-function studies of GnRH ligands and GnRH receptors and their expression patterns in different tissues add further intrigue to this hypothesis by indicating novel roles for GnRH such as neuromodulation of reproductive function and direct regulation of peripheral reproductive tissues. Surprises concerning the complexities of GnRH ligand and receptor function in reproductive endocrinology should continue to emerge in the future.

scholarly journals Conserved Amino Acid Residues that Are Important for Ligand Binding in the Type I Gonadotropin-Releasing Hormone (GnRH) Receptor Are Required for High Potency of GnRH II at the Type II GnRH Receptor

2007 ◽  
Vol 21 (1) ◽  
pp. 281-292 ◽  
Author(s):  
Sipho Mamputha ◽  
Zhi-liang Lu ◽  
Roger W. Roeske ◽  
Robert P. Millar ◽  
Arieh A. Katz ◽  
...  
Keyword(s):  
Inositol Phosphate ◽  
Gnrh Receptor ◽  
Type I ◽  
Type Ii ◽  
Amino Acid Residues ◽  
Binding Assays ◽  
Antagonist Activity ◽  
Conserved Residues ◽  
Gnrh Receptors ◽  
Mutant Receptors

Abstract GnRH I regulates reproduction. A second form, designated GnRH II, selectively binds type II GnRH receptors. Amino acids of the type I GnRH receptor required for binding of GnRH I (Asp2.61(98), Asn2.65(102), and Lys3.32(121)) are conserved in the type II GnRH receptor, but their roles in receptor function are unknown. We have delineated their functions using mutagenesis, signaling and binding assays, immunoblotting, and computational modeling. Mutating Asp2.61(97) to Glu or Ala, Asn2.65(101) to Ala, or Lys3.32(120) to Gln decreased potency of GnRH II-stimulated inositol phosphate production. Consistent with proposed roles in ligand recognition, mutations eliminated measurable binding of GnRH II, whereas expression of mutant receptors was not decreased. In detailed analysis of how these residues affect ligand-dependent signaling, [Trp2]-GnRH I showed lesser decreases in potency than GnRH I at the Asp2.61(97)Glu mutant. In contrast, [Trp2]-GnRH II showed the same loss of potency as GnRH II at this mutant. This suggests that Asp2.61(97) contributes to recognition of His2 of GnRH I, but not of GnRH II. GnRH II showed a large decrease in potency at the Asn2.65(101)Ala mutant compared with analogs lacking the C⋕O group of Gly10NH2. This suggests that Asn2.65(101) recognizes Gly10NH2 of GnRH II. GnRH agonists showed large decreases in potency at the Lys3.32(120)Gln mutant, but antagonist activity was unaffected. This suggests that Lys3.32(120) recognizes agonists, but not antagonists, as in the type I receptor. These data indicate that roles of conserved residues are similar, but not identical, in the type I and II GnRH receptors.

scholarly journals Gonadotrophin-releasing hormone receptors in GtoPdb v.2021.3

2021 ◽  
Vol 2021 (3) ◽  
Author(s):  
Laura H. Heitman ◽  
Adriaan P. IJzerman ◽  
Craig A. McArdle ◽  
Adam J Pawson
Keyword(s):  
Hormone Receptors ◽  
Gnrh Receptor ◽  
Type I ◽  
Gonadotropin Secretion ◽  
Gnrh Analogues ◽  
Releasing Hormone ◽  
Hormone Synthesis ◽  
Consequent Reduction ◽  
Gonadotrophin Releasing Hormone ◽  
Ancient Gene

GnRH1 and GnRH2 receptors (provisonal nomenclature [39], also called Type I and Type II GnRH receptor, respectively [85]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [85, 84, 114]. GnRH I (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 [85, 84, 114] including GnRH II (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 [85, 84, 114]. 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 [58]. 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 [58]. 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 [88]. Phylogenetic classifications divide GnRH receptors into three [85] or five groups [129] 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 [132].

scholarly journals Inhibition of Human Type I Gonadotropin-Releasing Hormone Receptor (GnRHR) Function by Expression of a Human Type II GnRHR Gene Fragment

Endocrinology ◽  
2005 ◽  
Vol 146 (6) ◽  
pp. 2639-2649 ◽  
Author(s):  
Adam J. Pawson ◽  
Stuart Maudsley ◽  
Kevin Morgan ◽  
Lindsay Davidson ◽  
Zvi Naor ◽  
...  
Keyword(s):  
Hormone Receptor ◽  
Gonadotropin Releasing Hormone ◽  
Type I ◽  
Type Ii ◽  
Gene Fragment ◽  
Releasing Hormone ◽  
Human Type ◽  
Gonadotropin Releasing Hormone Receptor

Homologous ligand regulation of gonadotrophin-releasing hormone receptors in vivo: relationship to gonadotrophin secretion and gonadal steroids

1985 ◽  
Vol 107 (1) ◽  
pp. 41-47 ◽  
Author(s):  
S. I. Naik ◽  
G. Saade ◽  
A. Detta ◽  
R. N. Clayton
Keyword(s):  
Gnrh Receptor ◽  
Peak Serum ◽  
Protein Synthesis Inhibitor ◽  
Normal Female ◽  
Releasing Hormone ◽  
Female Mice ◽  
Gnrh Receptors ◽  
Ovariectomized Mice ◽  
Serum Lh ◽  
Gonadotrophin Releasing Hormone

ABSTRACT A single injection of gonadotrophin-releasing hormone (GnRH) (60 ng s.c., 42·9 nmol) induced biphasic GnRH receptor regulation in normal intact adult female mice. A transient 22% receptor decrease occurred 30–60 min after injection of GnRH when peak serum decapeptide concentrations were reached (137 ± 41 (s.e.m.) ng/l). This GnRH receptor decrease occurred shortly after the peak serum LH values at 15–30 min. The subsequent rapid (within 1 h) return of GnRH receptor levels to normal suggested transient receptor occupancy by GnRH rather than true receptor loss. At 8 h after injection of GnRH a significant 35% increase in GnRH receptors was consistently observed, when serum GnRH levels were undetectable and serum LH had returned to basal levels. This receptor increase was not due to increased receptor affinity, and was prevented by a non-specific protein synthesis inhibitor. Ovariectomy, which caused a 50% fall in GnRH receptors (59·4 ± 4·9 fmol/pituitary gland in intact controls; 26·9 ± 2·6 in ovariectomized mice) abolished the induction by GnRH of its own receptors, although the initial transient decrease occurred over the period of the acute serum LH and FSH rise. Despite a 50% reduction in GnRH receptors in ovariectomized mice, increased serum gonadotrophin levels and responsiveness to GnRH were maintained, indicating dissociation between receptor changes and gonadotrophin levels. No GnRH receptor up-regulation was observed 8 h after a single GnRH injection (60 ng s.c.) in either intact or orchidectomized normal male mice. However, the same treatment doubled GnRH receptors in GnRH-deficient (hpg) female mice. While GnRH appears to up-regulate its own receptors by a direct action on pituitary gonadotrophs in the GnRH-deficient mouse its action in the normal female mouse pituitary appears secondary to stimulation of a gonadal product, presumably oestrogens. J. Endocr. (1985) 107, 41–47

Pituitary gonadotrophin-releasing hormone receptor up-regulation in vitro: dependence on calcium and microtubule function

1985 ◽  
Vol 107 (1) ◽  
pp. 49-56 ◽  
Author(s):  
L. S. Young ◽  
S. I. Naik ◽  
R. N. Clayton
Keyword(s):  
Luteinizing Hormone ◽  
Gnrh Receptor ◽  
Ionophore A23187 ◽  
Pituitary Cells ◽  
Hormone Release ◽  
Releasing Hormone ◽  
Luteinizing Hormone Release ◽  
Gnrh Receptors ◽  
Gonadotrophin Releasing Hormone

ABSTRACT Exogenous cyclic adenosine nucleotides increase gonadotrophin-releasing hormone (GnRH) receptors in intact cultured rat pituitary cells in a similar manner to that observed with GnRH itself. In this study the calcium and microtubule dependency of GnRH receptor up-regulation was examined in vitro. Treatment of pituitary cells in Ca2+ and serum-containing media with either GnRH (1 nmol/l), K+ (58 mmol/l) or dibutyryl cyclic AMP (dbcAMP; 1 mmol/l) for 7–10 h routinely resulted in a 50–100% increase in GnRH receptors. Incubation of pituitary cells with the calcium channel blocker verapamil, for 7 h, or the calcium chelator EGTA, for 10 h, had no effect on basal receptor levels but prevented the increase in GnRH receptors stimulated by either GnRH, K+ or dbcAMP. Luteinizing hormone release measured with the same stimulators over a 3-h period was prevented by both verapamil and EGTA. Calcium ionophore (A23187) increased GnRH receptors by 40–60% at low concentrations (10 and 100 nmol/l) while higher concentrations (10 and 100 μmol/l) reduced receptor levels. Luteinizing hormone release was not increased by receptor-stimulating concentrations of A23187, but was by higher concentrations (10 μmol/l). None of these pretreatments, for up to 10 h, impaired the subsequent LH response of the cells to increasing doses of GnRH. Vinblastine (1 μmol/l did not affect basal receptor levels but markedly reduced the increase in GnRH receptors stimulated by GnRH, K+ and dbcAMP. This concentration of vinblastine had no effect on LH release. These results indicate that receptor stimulation by GnRH, K+ and dbcAMP is a calcium-dependent process requiring the integrity of the microtubule system and there is a different calcium requirement for the processes of GnRH receptor up-regulation and LH secretion. J. Endocr. (1985) 107, 49–56

scholarly journals A novel human GnRH receptor homolog gene: abundant and wide tissue distribution of the antisense transcript

1999 ◽  
Vol 162 (1) ◽  
pp. 117-126 ◽  
Author(s):  
R Millar ◽  
D Conklin ◽  
C Lofton-Day ◽  
E Hutchinson ◽  
B Troskie ◽  
...  
Keyword(s):  
Receptor Gene ◽  
Gnrh Receptor ◽  
Receptor Subtypes ◽  
Type I ◽  
Type Ii ◽  
Antisense Transcripts ◽  
Antisense Orientation ◽  
Wide Range ◽  
Putative Intron ◽  
Intron 2

Gonadotropin releasing hormone (GnRH) regulates the reproductive system through a specific G-protein-coupled receptor (GPCR) in pituitary gonadotropes. The existence of two (or more) forms of GnRH in most vertebrates suggested the existence of GnRH receptor subtypes (I and II). Using sequence information for extracellular loop 3 of a putative Type II GnRH receptor from a reptile species, we have looked for a Type II GnRH receptor gene in the human genome EST (expressed sequence tag) database. A homolog was identified which has 45% and 41% amino acid identity with exons 2 and 3 of the known human GnRH pituitary receptor (designated Type I) and much lower homology with all other GPCRs. A total of 27 contiguous ESTs was found and comprised a continuous sequence of 1642 nucleotides. The EST sequences were confirmed in the cloned human gene and in PCR products of cDNA from several tissues. All EST transcripts detected were in the antisense orientation with respect to the novel GnRH receptor sequence and were highly expressed in a wide range of human brain and peripheral tissues. PCR of cDNA from a wide range of tissues revealed that intronic sequence equivalent to intron 2 of the Type I GnRH receptor was retained. The failure to splice out putative intron sequences in transcripts which spanned exon-intron boundaries is expected in antisense transcripts, as candidate donor and acceptor sites were only present in the gene when transcribed in the orientation encoding the GnRH receptor homolog. No transcripts extended 5' to the sequence corresponding to intron 2 of the Type I GnRH as the antisense transcripts terminated in poly A due to the presence of a polyadenylation signal sequence in the putative intron 2 when transcribed in the antisense orientation. These findings suggest that a Type II GnRH receptor gene has arisen during vertebrate evolution and is also present in the human. However, the receptor may have become vestigial in the human, possibly due to the abundant and universal tissue transcription of the opposite DNA strand to produce antisense RNA.

scholarly journals Gonadotrophin-releasing hormone receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

2019 ◽  
Vol 2019 (4) ◽  
Author(s):  
Laura H. Heitman ◽  
Adriaan P. IJzerman ◽  
Craig A. McArdle ◽  
Adam J. Pawson
Keyword(s):  
Hormone Receptors ◽  
Gnrh Receptor ◽  
Type I ◽  
Gonadotropin Secretion ◽  
Gnrh Analogues ◽  
Releasing Hormone ◽  
Hormone Synthesis ◽  
Consequent Reduction ◽  
Gonadotrophin Releasing Hormone ◽  
Ancient Gene

GnRH1 and GnRH2 receptors (provisonal nomenclature [35], also called Type I and Type II GnRH receptor, respectively [78]) have been cloned from numerous species, most of which express two or three types of GnRH receptor [78, 77, 107]. GnRH I (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 [78, 77, 107] including GnRH II (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 [78, 77, 107]. 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 [53]. 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 [53]. 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 [81]. Phylogenetic classifications divide GnRH receptors into three [78] or five groups [122] and highlight examples of gene loss through evolution, with humans retaining only one ancient gene.

scholarly journals Functional characterization and kinetic studies of an ancestral lamprey GnRH-III selective type II GnRH receptor from the sea lamprey, Petromyzon marinus

2006 ◽  
Vol 36 (3) ◽  
pp. 601-610 ◽  
Author(s):  
M R Silver ◽  
S A Sower
Keyword(s):  
Intact Cell ◽  
Functional Characterization ◽  
Kinetic Studies ◽  
Receptor Activation ◽  
Gnrh Receptor ◽  
Type I ◽  
Type Ii ◽  
Binding Assays ◽  
Gnrh Receptors ◽  
Series Of Experiments

The recently cloned lamprey GnRH receptor was shown to have several unique features, including the longest intracellular C-terminal tail (120 amino acids (aa)) of any previously described GnRH receptor. In the current study, a series of experiments were performed examining cAMP responses, binding kinetics, whole cell competitive binding assays and internalization studies of the lamprey GnRH receptor using a series of three C-terminal tail truncations (80 aa, 40 aa and 0 aa) to better describe the functional significance of this unique vertebrate GnRH receptor. Activation of the lamprey GnRH receptor was shown to stimulate cAMP production in a dose-dependant manner when treated with either lamprey GnRH-I (LogEC50 −6.57±0.15) or lamprey GnRH-III (LogEC50 −8.29±0.09). Truncation analysis indicated that the membrane proximal 40 aa of the lamprey GnRH receptor C-terminal tail contain a motif required for cAMP accumulation. Saturation binding assays using the wild type and truncated lamprey GnRH receptors revealed that all of three truncated lamprey GnRH receptors were capable of binding lamprey GnRH-I. Competitive, intact cell-binding assays suggested that the lamprey GnRH receptor is lamprey GnRH-III selective, based on the observed pharmacological profile: lamprey GnRH-III (Inhibitory constant (Ki) 0.708±0.245 nM)=chicken GnRH-II (Ki 0.765±0.160 nM) > mammalian GnRH (Ki 12.9±1.96 nM) > dAla6Pro9NEt mammalian GnRH (Ki 21.6±9.68 nM) > lamprey GnRH-I (Ki 118.0±23.6). Finally, the lamprey GnRH receptor was shown to undergo rapid ligand-dependant internalization, which was significantly diminished in the tail-less truncated form. We have shown from our current and our previous structural studies that this unique lamprey GnRH receptor shares several characteristics of both type I and type II GnRH receptors which suggests that this receptor has retained ancestral characteristics that can provide insight into the function and evolution of the vertebrate GnRH receptor family.

scholarly journals Bovine and Ovine Gonadotropin-Releasing Hormone (GnRH)-II Ligand Precursors and Type II GnRH Receptor Genes Are Functionally Inactivated

Endocrinology ◽  
2006 ◽  
Vol 147 (11) ◽  
pp. 5041-5051 ◽  
Author(s):  
Kevin Morgan ◽  
Robin Sellar ◽  
Adam J. Pawson ◽  
Zhi-Liang Lu ◽  
Robert P. Millar
Keyword(s):  
Gnrh Receptor ◽  
Gonadotropin Releasing Hormone ◽  
Type Ii ◽  
Releasing Hormone ◽  
Ligand Precursors
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