Two gonadotropin-releasing hormone receptor subtypes with distinct ligand selectivity and differential distribution in brain and pituitary in the goldfish (
            <i>Carassius auratus</i>
            )

Illing, Nicola; Troskie, Brigitte E.; Nahorniak, Carol S.; Hapgood, Janet P.; Peter, Richard; Millar, Robert P.

doi:10.1073/pnas.96.5.2526

Cited by 187 publications

(143 citation statements)

References 38 publications

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“…The non-mammalian GnRH receptors have Asp residues in both the H2 and H7 loci (15,16). The presence of the two Asp residues in these receptors raises the possibility that the nonmammalian GnRH receptors represent evolutionary intermediates between the conserved Asp-Asn arrangement found in most GPCRs and the Asn-Asp arrangement found in all mammalian GnRH receptors (1).…”

Section: Discussionmentioning

confidence: 99%

“…This result raised the possibility that charge repulsion was responsible for the observed phenotype. However, the presence of Asp at both positions in wild-type non-mammalian GnRH receptors (15,16) and in several other GPCRs (3) as well as in functional mutant GPCRs (9,10,14,17) indicates that the side chains in this microdomain, that are compatible with function, differ among GPCRs.…”

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confidence: 99%

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The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor

Flanagan¹,

Zhou²,

Chi³

et al. 1999

Journal of Biological Chemistry

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Structural microdomains of G protein-coupled receptors (GPCRs) consist of spatially related side chains that mediate discrete functions. The conserved helix 2/helix 7 microdomain was identified because the gonadotropin-releasing hormone (GnRH) receptor appears to have interchanged the Asp 2.50 and Asn 7.49 residues which are conserved in transmembrane helices 2 and 7 of rhodopsin-like GPCRs. We now demonstrate that different side chains of this microdomain contribute specifically to receptor expression, heterotrimeric G protein-, and small G protein-mediated signaling. An Asn residue is required in position 2.50(87) for expression of the GnRH receptor at the cell surface, most likely through an interaction with the conserved Asn 1.50 (53) residue, which we also find is required for receptor expression. Most GPCRs require an Asp side chain at either the helix 2 or helix 7 locus of the microdomain for coupling to heterotrimeric G proteins, but the GnRH receptor has transferred the requirement for an acidic residue from helix 2 to 7. However, the presence of Asp at the helix 7 locus precludes small G protein-dependent coupling to phospholipase D. These results implicate specific components of the helix 2/helix 7 microdomain in receptor expression and in determining the ability of the receptor to adopt distinct activated conformations that are optimal for interaction with heterotrimeric and small G proteins.The gonadotropin-releasing hormone (GnRH) 1 receptor belongs to the rhodopsin-like family of G protein-coupled receptors (GPCR) (1). This family includes the light-sensitive opsins, protease-activated receptors, and receptors for neurotransmitters, peptides, and glycoproteins. High resolution structural data have not yet been obtained for any GPCR. However, projection maps of rhodopsin, amino acid sequence alignment, and computational modeling indicate that GPCRs have 7 membrane-spanning ␣-helices (2-6). There is a high degree of homology within the transmembrane helices and certain amino acids are highly conserved throughout the family (2, 3, 7). This diverse family shares the common function of propagating a signal across lipid membranes and the amino acid side chains which are conserved among the GPCRs are likely to constitute key structural motifs which subserve this universal GPCR function. Several models of GPCRs, including the GnRH receptor (4, 8), have been constructed as aids for investigating receptor structure-function relations. Molecular models of GPCRs can be used to integrate experimental observations and generate structural hypotheses. However, the complexity of these structures and the limited number of experimentally determined constraints can lead to inconsistent behavior of the models (4, 7). To overcome these limitations, we have pursued the approach of identifying discrete structural motifs within receptor models, which might constitute functional microdomains. The microdomains are characterized in detail and subsequently incorporated into whole receptor models. In the GnRH receptor, for exa...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor

Flanagan¹,

Zhou²,

Chi³

et al. 1999

Journal of Biological Chemistry

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“…The positions of the extracellular (EC) and intracellular (IC) loop domains, transmembrane (TM) domains (dark blocks) and carboxyl terminal tail (C) are indicated. chicken and goldfish , Troskie et al 1997a, Illing et al 1999.…”

Section: Gene Structure Cdna Sequence and Amino Acid Sequencementioning

confidence: 99%

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

Millar

Conklin²,

Lofton–Day³

et al. 1999

Journal of Endocrinology

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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.

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“…In addition to type I GnRHR, the type II GnRHR (Fig. 2B) has been recently cloned in brain and pituitary from the goldfish (Carassius auratus, Illing et al 1999) and mammals such as the marmoset (Callithrix jacchus, Millar et al 2001) and the rhesus monkey (Macaca mulatto, Neill et al 2001). This type II receptor in goldfish shares a lower identity with mGnRHR (43%) and has distinct ligand selectivity.…”

mentioning

confidence: 99%

Potential role of gonadotrophin-releasing hormone (GnRH)-I and GnRH-II in the ovary and ovarian cancer.

Kang

Choi²,

Yang³

et al. 2003

Endocrine-Related Cancer

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Gonadotrophin-releasing hormone (GnRH) functions as a key neuroendocrine regulator of the hypothalamic-pituitary-gonadal axis. In addition to the hypothalamus and pituitary gland, GnRH and its receptor have been detected in other reproductive tissues including the gonads, placenta and tumours arising from these tissues. Recently, a second form of GnRH (GnRH-II) and type II GnRH receptor have been found in normal ovarian surface epithelium and neoplastic counterparts.

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Two gonadotropin-releasing hormone receptor subtypes with distinct ligand selectivity and differential distribution in brain and pituitary in the goldfish ( Carassius auratus )

Abstract: In the goldfish (Carassius auratus) the two endogenous forms of gonadotropin-releasing hormone (

Cited by 187 publications

References 38 publications

The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor

The Functional Microdomain in Transmembrane Helices 2 and 7 Regulates Expression, Activation, and Coupling Pathways of the Gonadotropin-releasing Hormone Receptor

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

Potential role of gonadotrophin-releasing hormone (GnRH)-I and GnRH-II in the ovary and ovarian cancer.

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