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Minireview: GnRH and GnRH Receptor Genes in the Human Genome

Department of Physiology and Biophysics, School of Medicine, University of Alabama, Birmingham, Alabama 35294-0005

Address all correspondence and requests for reprints to: Jimmy D. Neill, Department of Physiology & Biophysics, 812 MCLM, 1918 University Boulevard, University of Alabama, Birmingham, Alabama 35294-0005. E-mail: . neill{at}uab.edu

	Abstract

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
Four different GnRHs and one GnRH receptor are reported to be expressed in various mammals, whereas 13 GnRHs and numerous GnRH receptors have been identified in various nonmammalian vertebrates. The nucleotide sequencing of the human genome provided the opportunity to determine which of these peptides and receptors might be expressed in primates. Of the four GnRHs reportedly expressed in mammals, only GnRH I (mammalian GnRH) and GnRH II (chicken GnRH II) genes were identified in the human genome. Three GnRH receptor or receptor-like genes were identified: 1) the well-established GnRH I receptor gene located on chromosome 4; 2) an apparent GnRH II receptor gene located on chromosome 1, and; 3) a sterile GnRH II receptor-like homolog gene on chromosome 14. A cDNA cloned from monkey RNA that was 96% identical with the putative human GnRH receptor type II gene encoded a 379-amino acid G protein-coupled/7-transmembrane receptor having a C-terminal cytoplasmic tail. The experimentally expressed GnRH II receptor was functional with and specific for GnRH II, and, unlike the GnRH I receptor, desensitized to continuous GnRH treatment. GnRH II receptor mRNA is expressed ubiquitously in human tissues. Significant questions remain about the potential functions of the primate GnRH II receptor such as regulation of gonadotropin secretion, female sexual behavior, and tumor cell growth; also, about whether it is expressed as a full-length, functional gene transcript in humans.

	Introduction

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
MAMMALIAN GnRH I is the hypothalamic decapeptide that is the prime controller of reproductive function (1). It does this after secretion by the hypothalamus into the hypophysial portal circulation by binding and activating the GnRH I receptor, a member of the seven-transmembrane (7TM), G protein-coupled receptor (GPCR) family (2) that is expressed on the surface of pituitary gonadotrope cells (3). The resulting release of the gonadotropic hormones, FSH and LH, results in stimulation of the steroidogenic and gametogenic functions of the gonads of both sexes (1). Because of GnRH I’s rate-limiting role in reproductive processes, a very large number of GnRH analogs (thousands) have been studied (4). These have found several clinical uses including an important treatment for prostate cancer (5), and another as a component of the treatment regimen for ovulation induction in women undergoing in vitro fertilization (6).

Until recently, GnRH I was thought to be the sole hypothalamic messenger regulating reproductive processes in mammals. However, a form of GnRH originally isolated from chicken hypothalamus (cGnRH II) (7) was shown recently to be the most widely expressed GnRH among vertebrates (8) including mammals (9, 10). Indeed, in monkeys, GnRH II was shown to be expressed in the median eminence of the hypothalamus, a likely site for its secretion into the circulation of the pituitary gland; also, after GnRH II treatment of monkeys, a robust increase in the secretion of LH occurred (11), further increasing the likelihood that a second hypothalamic GnRH participates in the control of gonadotropin secretion.

Receptors of the 7TM, GPCR family for GnRH II have been cloned and sequenced from a number of fishes and amphibians (12, 13). Unlike the mammalian GnRH I receptor, these receptors have a C-terminal cytoplasmic tail that is phosphorylated in response to GnRH II followed by internalization and desensitization of the receptor (14). As with the GnRH I receptor, the GnRH II receptor couples to the Gq protein and therefore mediates the intracellular production of inositol phosphates.

The expression of GnRH II in mammals together with the existence of GnRH II receptors in nonmammalian vertebrates encouraged us to search for GnRH II receptors in mammals (15). Indeed, the recent sequencing of the human genome presented us with the seemingly simple task of determining whether sequences resembling the mammalian GnRH I receptor and the nonmammalian GnRH II receptor were present in the genome. Here we review our discovery of an apparent gene encoding a GnRH II receptor in the human genome, and its cloning, sequencing, and characterization from monkey tissues including the rhesus monkey anterior pituitary gland (15).

	A Putative GnRH II Receptor Gene in the Human Genome

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
The nucleotide sequences of the human GnRH I receptor (2) and the African catfish GnRH II receptor (12) were used to query the human genome sequence using the BLAST search programs in GenBank. Three GnRH receptor or receptor-like sequences were found (15). One was the GnRH I receptor localized to chromosome 4. Another was a putative GnRH II receptor gene on chromosome 1 that by comparison to the GnRH I receptor gene possessed three exons (Fig. 1) and had a 40% identity with the type 1 gene. A third was a sterile GnRH II receptor-like homolog gene previously identified as being 40% identical to exons 2 and 3 of the type 1 GnRH receptor gene, and to be encoded on the antisense DNA strand of the 3' untranslated region of the RBM8 gene on chromosome 14 (16, 17); the nucleotide sequences of these exons were 100% identical with exons 2 and 3 of the putative GnRH II receptor gene.

View larger version (14K): [in this window] [in a new window]   Figure 1. Exon/intron organization of the human GnRH II receptor gene and its derived amino acid sequences arrayed as the 7TM GnRH II receptor in monkeys.

	Molecular Cloning and Nucleotide Sequencing of a Primate GnRH II Receptor cDNA

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

View larger version (39K): [in this window] [in a new window]   Figure 2. Comparison of the 7TM, GPCR structures of green monkey GnRH II receptor and human GnRH I receptor. The darkened serine (S) and threonine (T) residues in the C-terminal tail of the GnRH II receptor are predicted sites of phosphorylation.

	GnRH Genes in the Human Genome

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
Before functional characterization of the putative GnRH II receptor, it was important to determine whether genes for GnRH(s) other than GnRH I or II were present in the human genome. The existence of GnRH I (18) and II (10) genes in the human genome was firmly established before the initiation (18) or completion (10) of sequencing of the human genome; the GnRH I gene resides on chromosome 8 (19), whereas GnRH II gene resides on chromosome 20 (10). These chromosomal localizations have been confirmed by us using the BLAST search program of the National Center for Biotechnology Information.

Eleven GnRH decapeptides in addition to GnRH I and II are established to exist in various vertebrates (20). Two of these, salmon GnRH (21, 22) and lamprey GnRH III (23), are reported to be expressed in mammals, although not with the rigor used to establish GnRH I and II expression. We searched the human genome for the presence of GnRH sequences matching those of the 13 known vertebrate peptides or of homologs matching the GnRH consensus sequence (Q-XX-S-XXXX-P-G-G-K-R, where X is any amino acid). Only GnRH I and II were found. The expression in the human of salmon GnRH and lamprey GnRH II seems doubtful, but some caution is required about this conclusion because 5–7% of the human genome remains unsequenced.

	Functional Characterization of the Primate GnRH II Receptor

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
COS-1 cells were transfected with the monkey GnRH II receptor cDNA, and [³H]-inositol phosphate production was measured in response to GnRHs (24). The potency was high for GnRH II (EC₅₀ = 0.58 nM), whereas it was low for GnRH I (EC₅₀ = 244 nM) (Table 1 and Fig. 3), thus demonstrating the functionality and specificity of the receptor for GnRH II (15). Indeed, GnRH II was 420-fold more potent than GnRH I. Two other GnRHs reportedly expressed in mammals, lamprey GnRH III (23) and salmon GnRH (21, 22), are active with the GnRH II receptor (Fig. 3), with salmon GnRH being more active (EC₅₀ = 23.4 nM) than GnRH I and lamprey GnRH III (Table 1 and Fig. 3); lamprey GnRH III is the least potent (Table 1 and Fig. 3), having an EC₅₀ of 4378 nM.

View larger version (21K): [in this window] [in a new window]   Figure 3. Activity of naturally occurring GnRHs with the GnRH II receptor. COS-1 cells were transfected with green monkey GnRH receptor cDNA, and [3H]-inositol phosphate accumulation was measured in response to the GnRHs.

	Synthetic GnRH I Superagonists and the GnRH II Receptor

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
An important question arising from the discovery of a GnRH II receptor in primates is the extent to which GnRH I analogs interact with the new receptor, and hence, whether they possess the specificity originally reported. Synthetic GnRH I superagonists thus were tested for activity with receptor cDNA-transfected cells (Table 1 and Fig. 4); with the GnRH II receptor, the EC₅₀ for Triptorelin (D-Trp⁶-GnRH I) was 7.5 nM, for D-Ala⁶,des Gly¹⁰-GnRH I was 16.7 nM, His⁵,D-Tyr⁶-GnRH I was 21.5 nM, and Buserilin was 48 nM. Thus, natural GnRH II (EC₅₀ = 0.58 nM) was more potent than any of the GnRH I superagonists, and natural GnRH I (EC₅₀ = 244 nM) was considerably less potent.

View larger version (22K): [in this window] [in a new window]   Figure 4. Activity of synthetic GnRH I agonists with the GnRH II receptor to stimulate [3H]-inositol accumulation in COS-1 cells.

	GnRH I Antagonists and the GnRH II Receptor

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
With the type II GnRH receptor, the most potent GnRH I antagonists (Antide and Cetrorelix) showed no inhibition of [³H]-inositol phosphate accumulation stimulated by the EC₅₀ concentration (2 nM) of GnRH II (Fig. 5 and Table 1). Only Coy antagonist 1 (IC₅₀ = 788 nM) showed complete inhibition of GnRH II (Fig. 5). The rat antagonist (IC₅₀ = 7618 nM) showed only partial inhibition of GnRH II activity (Fig. 5 and Table 1).

View larger version (21K): [in this window] [in a new window]   Figure 5. Activity of GnRH I antagonists to inhibit [3H]-inositol phosphate accumulation via GnRH II receptors in response to the EC50 concentration of GnRH II (2 nM). Coy antagonist 1 (N-Ac-Phe1-D-p-Cl-Phe2-D-Trp3,6)-GnRH I (peptide research code PRL-1334) was described by Zadina et al. (36), and Coy antagonist 2 (Ac-D-p-Cl-Phe1,2-D-Trp3-D-Lys6,D-Ala10)-GnRH I (peptide code PRL-1599) was described by Sun et al. (37). Rat antagonist [D-pGlu1,D-Phe2,D-Trp3,6]-GnRH I was obtained from Sigma (St. Louis, MO).

GnRH I antagonists also were tested for agonist activity with the GnRH II receptor (data not graphed). Antide, Cetrorelix, rat antagonist, and Coy antagonists 1 and 2 were tested. Only one showed activity (Coy antagonist 2) and, then only at a very large dose (EC₅₀ = 1,987 nM).

	Desensitization of the GnRH II Receptor

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
The mammalian GnRH II receptor (15) like the nonmammalian vertebrate GnRH II receptor (14), has a C-terminal cytoplasmic tail. In contrast, the mammalian GnRH I receptor is tail-less (2, 3). Previous work has shown that the tailed vertebrate receptor desensitizes, whereas the tail-less mammalian GnRH I receptor does not (14). To determine if the tailed mammalian type II GnRH receptor desensitized as would be expected from these considerations, we treated the monkey GnRH II receptor with GnRH II (10^-6 M) for 90 min, and measured [³H]-inositol phosphates at 10-min intervals for 90 min. As shown in Fig. 6, the monkey GnRH II receptor desensitized at about 60 min (Fig. 6). In contrast, the tail-less human GnRH I receptor used as a negative control did not desensitize during the 90-min period of GnRH I analog (Triptorelin, 10^-9 M) treatment (Fig. 6).

View larger version (18K): [in this window] [in a new window]   Figure 6. Upper graph, Desensitization of [3H]-inositol accumulation in COS-1 cells expressing type II GnRH receptors, and treated with a maximal dose of GnRH II (10-6 M) for 90 min. Lower graph, Failure of GnRH I receptor desensitization in COS-1 cells expressing the type I receptor, and treated with a maximal dose of GnRH I agonist (Triptorelin 10-9 M). With both types of receptors, the data are expressed as a percentage derived by dividing the total cellular uptake of [3H]-inositol into the [3H]-inositol phosphate accumulation. A single experiment representing a total of three is presented.

	GnRH II Receptor mRNA Expression in Human Tissues

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

View larger version (24K): [in this window] [in a new window]   Figure 7. Ubiquitous expression of GnRH II receptor mRNA expressed in human tissue arrays demonstrated using a 32P-labeled riboprobe specific for GnRH II receptor. The riboprobe represented the 7TM region of the receptor, and was hybridized to poly (A)+ RNA immobilized on nylon membranes unite on the y-axis are the relative intensities of hybridization as measured by densitometry of developed spots on film. The four bars at the far right represent tumor cell lines: leukemia, HL-60; HeLa, S3; colorectal adenocarcinoma, SW480; and lung adenocarcinoma, A549. The control group was comprised of eight separate RNA and DNA samples (yeast total RNA, yeast tRNA, Escherichia coli rRNA, Escherichia coli DNA, poly-rRNA, human Cot-1DNA, human DNA (100 and 500 mg); it failed to give a significant signal, attesting to the specificity of the labeled riboprobe hybridization to tissue poly (A)+ RNA samples.

	Potential Functions of the GnRH II Receptor

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

Another activity attributed to GnRH I that might involve GnRH II is participation in the induction of mating behavior (26, 27). Much skepticism about the physiological significance of this effect of GnRH I has arisen from the large doses required, the variability of the response, and from the observation that some GnRH antagonists induce rather than inhibit the behavior (28).

A final proposed effect of GnRH I that might involve GnRH II is suppression of cell growth in tumor cell lines (29). While it is true that GnRH I and its receptor are widely expressed in normal as well as tumorous tissues and cell lines (30, 31), GnRH I’s inhibitory effect on cell growth is modest, and large doses (micromolar) are usually required. Equally perplexing is the observation that GnRH I antagonists are as effective in this regard as GnRH I agonists (29).

Research is underway to more clearly define the function(s) of GnRH II and its receptor. Whatever answers are forthcoming from these studies, we predict that important advances in the understanding of the reproductive process will occur.

	Search for a Functional GnRH Receptor in Humans

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
Despite GnRH II receptor transcripts being detected in the extensive series of human tissues (Fig. 7), we have been unable so far using RT-PCR to find a full-length, appropriately processed transcript representing GnRH II receptor in human tissues. Most transcripts detected differ from the monkey GnRH II receptor cDNAs (Figs. 1 and 2) in one or more of four respects: 1) an in-frame stop codon is present in all transcripts as the ninth codon in the second exon (Fig. 1); 2) in many transcripts, in addition, the second intron is present (Fig. 1); 3) in some transcripts, the initiating ATG codon found in the monkey is out-of-frame in the human gene due to the presence of 5 guanines rather than the 4 in monkeys about 35 nucleotides downstream of the ATG codon, and; 4) some transcripts are spliced a few nucleotides downstream of the initiating ATG codon found in the monkey such that the initiating ATG codon is present in-frame in the human transcript; this same splicing event also eliminates much of the amino terminal tail and all of the first two TM regions; were it not for the stop codon in exon 2, a full-length 5TM receptor protein would be produced. Submission of the putative human GnRH II receptor gene sequence to two widely used gene analysis programs (GENSCAN; http://genes.mit.edu/GENSCAN.html and FGENESH+; http://genomic.sanger.ac.uk/gf/gfbs.html) resulted in the prediction that the stop codon in the second exon would be excluded by splicing downstream of it; however, such a transcript has not been found in our studies. All of these considerations lead to the conclusion that if a functional GnRH II receptor is expressed in humans, it may be a 5TM domain receptor lacking TM regions I and II. A precedent for this hypothesis is the report of a functional 5TM receptor lacking these TM regions (32).

It is difficult to believe that the GnRH II receptor RNAs transcribed in every tissue in the body are products of a nonfunctional gene. A definitive test of the existence of a functional GnRH II receptor in humans will be the description of a GnRH II-specific response in human cells or tissues. GnRH II response specificity will be a response that is more sensitive to GnRH II than to GnRH I and/or a GnRH II response that is not inhibited by GnRH I antagonists (see Fig. 5). A functional GnRH II receptor transcript should be demonstrable under such conditions.

In summary, our observation is that the GnRH receptor II gene is expressed in all tissues and cells studied so far as incompletely processed transcripts; from this observation arises the hypothesis that in some cell or tissue under the appropriate physiological conditions a properly processed GnRH II receptor will be found. Implicit in this hypothesis is the notion that nuclear processing of GnRH receptor II transcripts is regulated. There are precedents in the literature for such separation of transcription from posttranscriptional pre-mRNA processing (33, 34). Activation-induced splicing of preexisting TNF pre-mRNA has been reported for T lymphocytes after engagement of the T cell receptor; this effect could be mimicked by treatments that activate second messenger production (phorbol esters and ionomycin) (33). IL-1ß transcription and the processing of its pre-mRNA are separable events, and the processing into mature mRNA is regulated (34). Further studies are required to determine if processing of GnRH II receptor pre-mRNA into mature transcripts can be stimulated.

	Addendum

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 
After this manuscript was completed but before it was submitted for publication, a report (35) was published on the characterization of a GnRH II receptor cDNA in the marmoset, a New World monkey. While largely confirmatory of our earlier publication (15), importantly, it also provides evidence for expression of the GnRH II receptor protein in the human. The marmoset GnRH receptor cDNA encodes a 380- amino acid protein G protein-coupled, 7TM receptor bearing a C-terminal tail. Its nucleotide sequence is 93% identical with the monkey sequences reported by us (15). The marmoset receptor couples to inositol phosphate production, and shows specificity for GnRH II: GnRH II was approximately 40-fold more potent than GnRH I. The human tissue distribution of mRNA representing GnRH II receptor included the brain, heart, and pancreas; in contrast to our results (Fig. 6), little RNA was found in placenta, lung, liver, skeletal muscle, and kidney.

The most significant new finding of this study (35) was the presence of GnRH II receptor immunoreactivity in the human pituitary and brain. The receptor antibody was prepared against a peptide representing the third extracellular loop of the putative human GnRH II receptor. These results strongly support the expression of the GnRH II receptor in humans despite our inability so far to identify a full-length, appropriately processed GnRH II receptor transcript in the human including the brain and pituitary.

	Acknowledgments

 
I thank L. Wayne Duck, Jeffrey C. Sellers, and Lois C. Musgrove for their invaluable contributions to these studies; Dr. David Coy (Tulane University, New Orleans, LA), for GnRH antagonists; and Patricia Matthews for preparing the manuscript.

	Footnotes

 
This work was supported by a Research Grant from the National Institutes of Health (HD-37121).

Abbreviations: GPCR, G protein-coupled receptor; TM, transmembrane.

Received October 2, 2001.

Accepted for publication November 26, 2001.

	References

Top Abstract Introduction A Putative GnRH II... Molecular Cloning and Nucleotide... GnRH Genes in the... Functional Characterization of... Synthetic GnRH I Superagonists... GnRH I Antagonists and... Desensitization of the GnRH... GnRH II Receptor mRNA... Potential Functions of the... Search for a Functional... Addendum References

 

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