Gonadotropin-Releasing Hormone: Molecules and Receptors

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GnRH-dependent up-regulation of nitric oxide synthase I level in pituitary gonadotrophs mediates cGMP elevation during rat proestrus. Evidence that gonadotropin-releasing hormone stimulates gene expression and levels of active nitric oxide synthase type I in pituitary gonadotrophs, a process altered by desensitization and, indirectly, by gonadal steroids. Gonadotropin-releasing hormone-induced activation of diacylglycerol kinase-zeta and its association with active c-src.

Cytoskeletal reorganization dependence of signaling by the gonadotropin-releasing hormone receptor. Nuclear stabilization of beta-catenin and inactivation of glycogen synthase kinase-3beta by gonadotropin-releasing hormone: targeting Wnt signaling in the pituitary gonadotrope. Circhoral oscillations of plasma LH levels in the ovariectomized rhesus monkey. Endocrinology 87 — The temporal relationship between gonadotropin releasing hormone GnRH and luteinizing hormone LH secretion in ovariectomized ewes.

Gonadotropin Releasing Hormone Receptor

Hypophysial responses to continuous and intermittent delivery of hypopthalamic gonadotropin-releasing hormone. Mechanisms for pulsatile regulation of the gonadotropin subunit genes by GNRH1. Biol Reprod 74 — Regulation of rat pituitary gonadotropin-releasing hormone receptor mRNA levels in vivo and in vitro. The frequency of gonadotropin-releasing-hormone stimulation differentially regulates gonadotropin subunit messenger ribonucleic acid expression.

A pulsatile gonadotropin-releasing hormone stimulus is required to increase transcription of the gonadotropin subunit genes: evidence for differential regulation of transcription by pulse frequency in vivo. Shupnik MA. Effects of gonadotropin-releasing hormone on rat gonadotropin gene transcription in vitro: requirement for pulsatile administration for luteinizing hormone-beta gene stimulation. Mol Endocrinol 4 — Differential regulation of gonadotropin subunit gene expression by gonadotropin-releasing hormone pulse amplitude in female rats.

Gonadotropin-releasing hormone differentially regulates expression of the genes for luteinizing hormone alpha and beta subunits in male rats.

Gonadotropin-Releasing Hormone: Molecules and Receptors, Volume - 1st Edition

Frequency and amplitude of gonadotropin-releasing hormone stimulation and gonadotropin secretion in the rhesus monkey. Differential control of luteinizing hormone and follicle-stimulating hormone secretion by luteinizing hormone-releasing hormone pulse frequency in man. Differential regulation of gonadotropin subunit gene promoter activity by pulsatile gonadotropin-releasing hormone GnRH in perifused L beta T2 cells: role of GnRH receptor concentration. GnRH signaling, the gonadotrope and endocrine control of fertility.

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Front Neuroendocrinol 31 — Gonadotropin-releasing hormone and protein kinase C signaling to ERK: spatiotemporal regulation of ERK by docking domains and dual-specificity phosphatases. Frequency-dependent regulation of follicle-stimulating hormone beta by pulsatile gonadotropin-releasing hormone is mediated by functional antagonism of bZIP transcription factors.

Mol Cell Biol 30 — Pulse sensitivity of the luteinizing hormone beta promoter is determined by a negative feedback loop Involving early growth response-1 and Ngfi-A binding protein 1 and 2. Module dynamics of the GnRH signal transduction network. J Theor Biol — Plasma membrane expression of gonadotropin-releasing hormone receptors: regulation by peptide and nonpeptide antagonists. Mol Endocrinol 24 — A mathematical model for LH release in response to continuous and pulsatile exposure of gonadotrophs to GnRH.

Theor Biol Med Model 1 Eur J Pharmacol — Gonadotropin-releasing hormone receptor-coupled gene network organization. Ubiquitination and proteasomal degradation of endogenous and exogenous inositol 1,4,5-trisphosphate receptors in alpha T anterior pituitary cells. Muratani M, Tansey WP. How the ubiquitin-proteasome system controls transcription. Nat Rev Mol Cell Biol 4 — Proteasome regulation of dynamic transcription factor occupancy on the GnRH-stimulated luteinizing hormone beta-subunit promoter.

Gonadotropin-releasing hormone pulse sensitivity of follicle-stimulating hormone-beta gene is mediated by differential expression of positive regulatory activator protein 1 factors and corepressors SKIL and TGIF1. Mol Endocrinol 25 — Macian F. NFAT proteins: key regulators of T-cell development and function. Nat Rev Immunol 5 — Biochem Soc Trans 34 — Sensitivity of NFAT cycling to cytosolic calcium concentration: implications for hypertrophic signals in cardiac myocytes.

Biophys J 96 — Dual role of calmodulin in autophosphorylation of multifunctional CaM kinase may underlie decoding of calcium signals. Neuron 12 — EMBO J 19 — Oncogene 20 — Mol Cell Biol 25 — NFAT functions as a working memory of a signals in decoding a oscillation. EMBO J 22 — Noise propagation and scaling in regulation of gonadotrope biosynthesis. Biophys J 93 — Calcium oscillations in pituitary gonadotrophs: comparison of experiment and theory. The GnRH promoter: target of transcription factors, hormones, and signaling pathways. Signaling responses to pulsatile gonadotropin-releasing hormone in LbetaT2 gonadotrope cells.

Mol Cell Neurosci 3 — Oxytocin receptor-mediated activation of phosphoinositidase C and elevation of cytosolic calcium in the gonadotrope-derived alphaT cell line. Wortmannin-sensitive and -insensitive steps in calcium-controlled exocytosis in pituitary gonadotrophs: evidence that myosin light chain kinase mediates calcium-dependent and wortmannin-sensitive gonadotropin secretion. G proteins and autocrine signaling differentially regulate gonadotropin subunit expression in pituitary gonadotrope. Denef C. Paracrinicity: the story of 30 years of cellular pituitary crosstalk.

J Neuroendocrinol 20 :1— Isolation of a novel 38 residue-hypothalamic polypeptide which stimulates adenylate cyclase in pituitary cells.

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  • Isolation of a neuropeptide corresponding to the N-terminal 27 residues of the pituitary adenylate cyclase activating polypeptide with 38 residues PACAP Biol Reprod 84 — Endocr Rev 21 — Guide to receptors and channels GRAC , 5th edition. Br J Pharmacol Suppl 1 :S1— Rawlings SR, Hezareh M. Endocr Rev 17 :4— Ann N Y Acad Sci — Dickson L, Finlayson K. Pharmacol Ther — Cell — Protein kinase C-independent stimulation of activator protein-1 and c-Jun N-terminal kinase activity in human endometrial cancer cells by the LHRH agonist triptorelin. Eur J Endocrinol — Evidence for localized calcium mobilization and influx in single rat gonadotropes.

    Pituitary adenylate cyclase-activating polypeptide specifically increases cytosolic calcium ion concentration in rat gonadotropes and somatotropes. Pituitary adenylate cyclase-activating polypeptide effects in pituitary cells: modulation by gonadotropin-releasing hormone in alpha T cells. Effects of pituitary adenylate cyclase-activating polypeptide in the pituitary: activation of two signal transduction pathways in the gonadotrope-derived alpha T cell line.

    Paracrine control of gonadotrophs. Semin Reprod Med 25 — Transcriptional regulation of follistatin expression by GnRH in mouse gonadotroph cell lines: evidence for a role for cAMP signaling. Pituitary adenylate cyclase-activating polypeptide PACAP potentiates the gonadotropin-releasing activity of luteinizing hormone-releasing hormone.

    Pituitary adenylate cyclase-activating polypeptide: a key player in reproduction? Tsujii T, Winters SJ. Effects of pulsatile pituitary adenylate cyclase activating polypeptide PACAP on gonadotropin secretion and subunit mRNA levels in perifused rat pituitary cells.

    Life Sci 56 — Trends Endocrinol Metab 7 — Peptides 28 — Ets-related protein Elk-1 is homologous to the c-fos regulatory factor p62TCF. Effects of pituitary adenylate cyclase-activating polypeptide on gonadotropin secretion and subunit messenger ribonucleic acids in perifused rat pituitary cells.

    Regul Pept — Pulse frequency-dependent gonadotropin gene expression by adenylate cyclase-activating polypeptide 1 in perifused mouse pituitary gonadotroph LbetaT2 cells. Peptides 31 — Evidence that pituitary adenylate cyclase activating polypeptide suppresses follicle-stimulating hormone-beta messenger ribonucleic acid levels by stimulating follistatin gene transcription. Mol Cell Biochem — C-type natriuretic peptide: an important neuroendocrine regulator? Trends Endocrinol Metab 11 — Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions.

    Endocr Rev 27 — Baxter GF. The natriuretic peptides. Basic Res Cardiol 99 — Dwarfism and early death in mice lacking C-type natriuretic peptide. Molecular characterisation and functional interrogation of a local natriuretic peptide system in rodent pituitaries, alphaT and LbetaT2 gonadotroph cells.

    Critical roles of the guanylyl cyclase B receptor in endochondral ossification and development of female reproductive organs. J Neuroendocrinol 6 — Cyclic guanosine monophosphate production in the pituitary: stimulation by C-type natriuretic peptide and inhibition by gonadotropin-releasing hormone in alpha T cells. Receptor-mediated stimulatory effect of atrial natriuretic factor, brain natriuretic peptide, and C-type natriuretic peptide on testosterone production in purified mouse Leydig cells: activation of cholesterol side-chain cleavage enzyme. Isolation, mapping, and regulated expression of the gene encoding mouse C-type natriuretic peptide.

    Natriuretic peptides in the human testis: evidence for a potential role of C-type natriuretic peptide in Leydig cells. J Clin Endocrinol Metab 81 — Estradiol induces C-type natriuretic peptide gene expression in mouse uterus. C-type natriuretic peptide and the guanylyl cyclase receptors in the rat ovary are modulated by the estrous cycle. Biol Reprod 56 — Hormonal regulation of natriuretic peptide system during induced ovarian follicular development in the rat. Gestational regulation of the gene expression of C-type natriuretic peptide in mouse reproductive and embryonic tissue.

    Regul Pept :9— Walther T, Stepan H. C-type natriuretic peptide in reproduction, pregnancy and fetal development. Regul Pept 84 — Nitric oxide synthase in the rat anterior pituitary gland and the role of nitric oxide in regulation of luteinizing hormone secretion. Knowles RG, Moncada S. Nitric oxide synthases in mammals. Murad F.

    Gonadotropin-Releasing Hormone and GnRH Receptor: Structure, Function and Drug Development

    The Albert Lasker medical research awards. Signal transduction using nitric oxide and cyclic guanosine monophosphate. JAMA — Nitric oxide synthase in the human pituitary gland. Pituitary adenylate cyclase-activating polypeptide stimulates nitric-oxide synthase type I expression and potentiates the cGMP response to gonadotropin-releasing hormone of rat pituitary gonadotrophs.

    Isolation and characterization of a rat nitric oxide synthase type I gene promoter that confers expression and regulation in pituitary gonadotrope cells. The rat pituitary promoter of the neuronal nitric oxide synthase gene contains an Sp1-, LIM homeodomain-dependent enhancer and a distinct bipartite gonadotropin-releasing hormone-responsive region.

    The orphan nuclear receptor, steroidogenic factor 1, regulates neuronal nitric oxide synthase gene expression in pituitary gonadotropes. Ceccatelli S. Expression and plasticity of NO synthase in the neuroendocrine system.

    Mechanisms of Hormone Action

    Brain Res Bull 44 — Inhibition of nitric oxide facilitates LH release from rat pituitaries. Life Sci 61 — Chronic nitric oxide deficiency is associated with altered leutinizing hormone and follicle-stimulating hormone release in ovariectomized rats. GnRH and gonadotropin release is decreased in chronic nitric oxide deficiency. Effect of oxytocin on nitric oxide activity controlling gonadotropin secretion in humans. Eur J Clin Invest 33 — Nitric oxide NO stimulates gonadotropin secretion in vitro through a calcium-dependent, cGMP-independent mechanism.

    Neuroendocrinology 68 — Gonadotropin-releasing hormone GnRH antagonists promote proapoptotic signaling in peripheral reproductive tumor cells by activating a Galphai-coupling state of the type I GnRH receptor. Cancer Res 64 — The deletion causes a frameshift in the open reading frame, thus generating new coding sequence for a further 75 amino acids. The truncated cDNA arises from alternative splicing that uses a cryptic 3-prime splice site in exon 2.

    The splice variant was incapable of ligand binding and signal transduction. Coexpression of wildtype and truncated proteins in transiently or stably transfected cells, resulted in impaired signaling via the wildtype GNRHR by reducing maximal agonist-induced inositol phosphate accumulation. The clones contained the entire protein coding region of the GNRHR gene, which is distributed among 3 exons and spans over The 2 introns, measuring 4.

    Genomic Southern blot analysis demonstrated the presence of a single copy of the gene in the human genome. Fan et al. The gene appears to have large 5-prime and 3-prime untranslated regions, including, respectively, multiple transcription initiation sites and polyadenylation signals. Kaiser et al. Furthermore, using linkage analysis of single-strand conformation polymorphisms, they localized the murine homolog to mouse chromosome 5.

    By in situ hybridization using a biotinylated cDNA probe, Morrison et al. By fluorescence in situ hybridization using a larger genomic clone as a probe, Leung et al. Kottler et al.

    Gonadotropin-Releasing Hormone: Molecules and Receptors

    Genetic analysis of the YACs showed that the gene lies between D4S and D4S, which are located 76 and 77 cM, respectively, from the end of the short arm of chromosome 4. Furthermore, by fluorescence in situ hybridization, Kottler et al. The growth of sex hormone-dependent tumors is inhibited by analogs of luteinizing hormone-releasing hormone LHRH; The use of LHRH agonists for treatment of prostatic and breast cancer is based on suppression of pituitary-gonadal function and the consequent creation of a state of sex-steroid deficiency.

    In addition, LHRH agonists and antagonists exert a direct effect on these tumors that probably is mediated by specific high-affinity LHRH receptors found on these cells. LHRH agonists and antagonists also suppress the growth of experimental pancreatic cancers. Szende et al. These binding sites appear to be LHRH receptors since electron microscopic immunohistochemical studies show that an antibody to the LHRH receptor reacted with sites in the nucleus of pancreatic tumor cells.

    Maji et al. In a sister and brother with normosmic idiopathic hypogonadotropic hypogonadism HH7; , de Roux et al. Layman et al. In 3 sibs from a kindred with isolated HH, Caron et al. In a brother and 2 sisters with HH, de Roux et al. In a male patient with complete HH, Pralong et al. In a woman with complete HH, Kottler et al. In a year-old male with a mild form of hypogonadotropic hypogonadism, Pitteloud et al. Costa et al. To determine the frequency and distribution of GNRHR mutations in a heterogeneous population of patients with idiopathic hypogonadotropic hypogonadism, Beranova et al.

    Forty-eight of the patients had a normal sense of smell, whereas the remaining 60 had anosmia or hyposmia Kallmann syndrome. Five unrelated probands 3 men and 2 women , all normosmic, were documented to have changes in the coding sequence of the GNRHR. The remaining 3 probands with GNRHR mutations were from a subgroup of 18 patients without evidence of familial involvement, indicating a prevalence of 3 of 18 Among the 5 individuals bearing GNRHR mutations, a broad spectrum of phenotypes was noted, including testicular sizes that varied from prepubertal to the normal adult male range.

    Three probands had compound heterozygous mutations, and 2 had homozygous mutations. Of the 8 DNA sequence changes identified, 4 were novel. Janovick et al. The pharmacologic agent used was a small, membrane-permeant molecule, originally designed as an orally active, nonpeptide receptor antagonist, but is believed to function as a folding template, capable of correcting the structural defects caused by the mutations and thereby restoring function.

    The rescued receptor, stabilized in the plasma membrane, coupled ligand binding to activation of the appropriate effector system. For comparison, low-, intermediate-, or high-affinity peptide antagonists of GNRHR that do not penetrate the cell were unable to effect rescue, as was a nonbinding peptidomimetic congener of the rescue agent; this latter effect demonstrates specificity of the rescue agent. Bedecarrats et al. Despite similar impairment of GNRH-stimulated inositol phosphate production, dose-response analyses indicated that QR and RQ both reduced the sensitivity of the FSH-beta gene promoter to a greater extent than LH-beta or the alpha-glycoprotein subunit alpha-GSU; , suggesting the involvement of more than one signaling pathway.

    The authors concluded that differential stimulation of LH-beta, FSH-beta, and alpha-GSU gene expression may contribute to the varied phenotypes observed among patients harboring these mutations. Leanos-Miranda et al. The dominant-negative effect of the naturally occurring receptor mutants occurred only for the wildtype GNRHR, which has intrinsic low maturation efficiency. The data suggested that this dominant-negative effect accompanies the diminished plasma membrane expression as a recent evolutionary event.

    All observed associations were relatively modest and only nominally statistically significant. In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively , Seminara et al. The apparently unaffected parents were heterozygous for the mutations. Pitteloud et al. Mutation analysis of the children of the younger sister revealed that her unaffected daughter, who had undergone normal puberty, was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene, and that her prepubertal year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in GNRHR but did not have any mutations in the FGFR1 gene.

    In a sister and brother with hypogonadotropic hypogonadism HH7; , de Roux et al. Both residues are highly conserved and are located in the first extracellular and third intracellular loop of the GNRH receptor, respectively. The unaffected parents and sister, who were clinically and endocrinologically normal, were each heterozygous for 1 of the mutations.

    In 2 sisters with primary amenorrhea and no breast development at 25 and 18 years of age, respectively, Seminara et al. Mutation analysis of the children of the younger sister revealed that her unaffected daughter, who underwent normal puberty, was heterozygous for the mutation in FGFR1 but had no mutations in the GNRHR gene, and that her prepubertal year-old twin sons, born without cryptorchidism or microphallus, were each heterozygous for 1 of the mutations in the GNRHR gene but did not have any mutations in the FGFR1 gene. In a year-old male with mild HH, who had hypogonadal testosterone levels, detectable but apulsatile gonadotropin secretion, and normal testicular size, and who developed sperm after treatment with CG see , Pitteloud et al.

    The authors noted that de Roux et al. In 4 Brazilian sibs with partial HH, Costa et al. In 2 brothers with severe HH, Karges et al. For discussion of the argto-gln RQ mutation in the GNRHR gene that was found in compound heterozygous state in patients with hypogonadotropic hypogonadism HH7; by de Roux et al. De Roux et al. In 2 brothers with HH7, Lin et al. The proband, who presented at 15 years of age with delayed puberty, responded to a short course of testosterone with appropriate progress through puberty, whereas his younger brother showed little response after treatment.

    Lin et al. In 4 sibs with hypogonadotropic hypogonadism HH7; , Layman et al. The mutations were not found in an unaffected sib or in 75 unrelated controls. At least 1 of the affected females ovulated in response to exogenous gonadotropins. The 2 GNRHR mutations had minimal effects on receptor affinity, but receptor expression was decreased for both. A direct comparison between the wild-type and mutant receptors, made by plotting the percentage of bound tracer internalized with increasing time of incubation, showed that the cells expressing LI and LV receptors internalized the labeled agonist at slower rates Fig.

    These results suggested that Leu is not a major determinant of internalization of the GnRH receptor. Internalization of wild-type and Leu mutant mouse GnRH receptors. Panel A , effects of Leu substitutions on time course of internalization by mouse receptors. Panel B , percentage of internalization at 60 min for the wild-type and mutant GnRH receptors from panel A. The functional role of the conserved Leu in the amino-terminal region of the third intracellular loop of the GnRH receptor was analyzed in mutant receptors in terms of its cell-surface expression, ligand binding, agonist-induced signal transduction, and internalization.

    Our findings indicate that signal generation efficiency, measured by the stimulation of inositol phosphate production by GnRH, was significantly impaired in the LI and LV mutant receptors. The binding properties of these receptors for the GnRH agonist were largely unchanged from those of the wild-type receptor, indicating that these substitutions did not alter the integrity of the receptor.

    Thus, it appears that Leu is critical for G protein coupling of the GnRH receptor and subsequent phospholipase C activation. Although substantial reductions in signal transduction efficiency were observed for the Ile and Val mutants, the partial retention of inositol phosphate signaling indicates that other regions or residues in the intracellular loops are involved in G protein activation. This was also the case for receptor internalization, which was significantly decreased but not abolished.

    A large body of literature on various GPCRs, recently reviewed by Wess 10 , indicates that the IL3 loop is of critical importance for proper G protein recognition, but is not usually the sole determinant of the coupling properties of a given receptor. Rather, the IL3 appears to act in a cooperative manner with other receptor domains to permit optimum coupling and selectivity. For example, in muscarinic and catecholamine receptors, both the amino and carboxyl termini of IL3, as well as some regions within IL2, have been shown to be important in G protein binding and activation ; for the rhodopsin receptor, both IL2 and IL3 appear to interact with the G protein transducin, G t The involvement of several intracellular loops for optimal signaling also applies to other GPCRs, such as the metabotropic glutamate receptor 1, in which IL2 of the receptor cooperates with other intracellular domains in coupling to G proteins Impairment in signaling was also observed following replacement of the conserved hydrophobic residue Leu , in the middle of IL2 with Asp or Ala In another study, co-expression of the wild-type human GnRH receptor and a splice variant lacking one-third of the carboxyl-terminal region, including IL3, significantly reduced the signaling ability of the wild-type receptor, presumably due to direct physical interactions between the intracellular loops of the wild-type and truncated forms of the receptor These results suggest that a specific conformation of IL2 is necessary for productive coupling to G protein s.

    In another study, deletion of the carboxyl portion Ala —Leu of IL3 of the rat GnRH receptor was found to abolish receptor binding and signaling, probably due to lack of expression of the mutant receptor Additionally, mutation of Ala corresponding to Ala in the mouse or rat receptor in the carboxyl-terminal region of IL3 in the human GnRH receptor led to impaired G protein-coupled signaling Thus, variable effects on receptor function have been observed following mutation of the conserved residue in different receptors.

    It has been shown that the second and third intracellular loops of several GPCRs, particularly their NH 2 - and COOH-terminal regions, and sometimes the membrane proximal region in the carboxyl terminus of the receptor, are important sites for G protein coupling and specificity In particular, the amino-terminal region of IL3 is generally considered to be an important determinant of G protein coupling and specificity. In many GPCRs, the amino acids in this region form an amphiphilic helix with nonpolar and positively charged surfaces.

    Mutational studies targeting the charged surface have not shown major perturbations in the functional characteristics of the mutant receptors In the AT 1a receptor, replacement of all positively charged residues in this region did not influence the ability of the receptor to activate G proteins However, the presence of a conserved apolar amino acid in this region, corresponding to the Leu residue analyzed in the present study, was shown to be critical in the agonist-induced activation of the AT 1a receptor Replacements of the conserved leucine with charged amino acids or the short apolar amino acid, alanine, did not impair AT 1a receptor expression but interfered with its internalization and signal transduction functions.

    In the present study, these replacements caused impairment of both expression and function of the GnRH receptor. Thus, the role of this residue in receptor activation is conserved in distantly related GPCRs. Mammalian GnRH receptors, like other GPCRs, undergo endocytosis following agonist binding, but their internalization proceeds relatively slowly. Although receptor internalization and signaling both require the active conformation of the receptor, the structural determinants of the two processes are not identical.

    Some of these motifs may be common or overlapping, and other might be distinct. For example, sequences in the cytoplasmic tail of the angiotensin AT 1a receptor were found to be critical determinants of receptor internalization, but had no significant role in angiotensin II-induced signal transduction Conversely, mutant receptors with impaired signaling ability were shown to undergo rapid endocytosis On the other hand, mutation of the highly conserved Tyr in the fifth transmembrane domain impaired agonist-induced internalization of the mutant AT 1a receptor and also abolished its ability to mediate inositol phosphate response In the GnRH receptor, several mutations associated with impairment of signaling were found to concomitantly decrease receptor internalization 17 , In this context, it is noteworthy that in the present study the extent of internalization was reduced but still readily demonstrable, and the EC 50 values for GnRH-induced inositol phosphate production were significantly increased.

    Analysis of the Leu mutant receptors revealed that receptor internalization and inositol phosphate signaling have a common amino acid requirement at this position, suggesting that mutations of this residue interfere with an event that affects both processes. Despite the parallel impairment of the signaling properties and internalization of the LI and LV receptors, replacement of this single amino acid did not cause a major perturbation of receptor structure, as indicated by the retention of high binding affinity for the GnRH agonist.

    The roles of the individual amino acids surrounding the predicted hydrophobic cluster will be examined in future studies. Such molecular models can assist in defining the structural basis for the receptor phenotypes observed in mutagenesis experiments. It has been proposed that conserved amino acid residues serve to maintain the general topological structure of the GPCRs, and certain of their functions. To maintain such a well packed apolar cluster Fig. Mutations may cause rearrangement of the apolar cluster and consequently induce structural change s in the receptor.

    For the Leu to Ile or Val GnRH receptor mutants, which retain binding and possess agonist affinities similar to that of the wild-type receptor, it is assumed that the overall structure of the receptor is not perturbed and the ligand binding site is maintained. However, the decreased InsP production and internalization of these mutants may reflect the structural change induced by the mutations.

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    Conversely, the mutant receptors Leu to Ala, Arg, or Asp exhibit no detectable agonist binding, suggesting that these substitutions disrupt the apolar microenvironment and induce significant structural change that impairs surface expression of the receptor protein. In the structural context, these results suggest that mutations of the conserved Leu to Ile or Val are tolerated for maintaining the hydrophobic environment, as these receptors were well expressed. However, the mutant receptors are less efficient in signaling than the wild-type receptor and give submaximal InsP responses, suggesting that they cannot adopt the agonist-induced high affinity active conformation that is endowed by leucine interactions.

    Molecular modeling of the GnRH receptor. Three-dimensional computational model of transmembrane domains V and VI of the mouse GnRH receptor, illustrating the hydrophobic cluster surrounding the conserved residue Leu shown in blue. A comparison of the sequences of the amino-terminal region of IL3 of a subfamily of GPCRs 13 has revealed that many such receptors have a nonpolar residue in the position corresponding to Leu of the GnRH receptor, identified by its distance from the conserved Pro and Tyr residues in the fifth transmembrane domain Tyr is replaced by Asn in the GnRH receptor.

    The identity of this apolar amino acid in GPCRs shows some correlation with the receptor-G protein coupling specificity, but this is not strictly conserved When this comparison was extended, it was noted that the fourth residue located upstream of the conserved apolar amino acid corresponding to Leu is almost invariably an aliphatic usually Ile residue in GPCRs.

    In summary, the data presented in this study provide evidence for the importance of a highly conserved apolar residue Leu located in the amino-terminal region of the third intracellular loop, in the expression, agonist-mediated signaling, and internalization of the GnRH receptor. These findings are in accordance with the predicted role of this residue, based on its location in a hydrophobic cluster predicted by molecular modeling of the GnRH receptor.

    The concomitant impairment of expression, internalization, signaling, and G protein coupling of the mutant GnRH receptor suggest that this hydrophobic residue is an important determinant of multiple aspects of its activation mechanism. Section solely to indicate this fact. You'll be in good company. Journal of Lipid Research. Catt and Krishan K. Figure 1 Secondary structure of the GnRH receptor. Previous Section Next Section. Receptor Expression In addition to radioligand binding assays, an indirect ELISA protocol was used to quantify the expression of epitope-tagged wild-type or mutant GnRH receptors in the plasma membrane.

    Binding to COS-1 Cell Membranes For membrane binding experiments, cells were cultured and transfected in mm cell culture dishes.

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