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Biol Reprod 2003, 10.1095/biolreprod.103.024471
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BIOLOGY OF REPRODUCTION 70, 861–866 (2004)
DOI: 10.1095/biolreprod.103.024471
© 2004 by the Society for the Study of Reproduction, Inc.

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Regulation of Luteinizing Hormone/Human Chorionic Gonadotropin Receptor Expression: A Perspective1

K.M.J. Menon2,3, Utpal M. Munshi3, Christine L. Clouser3, and Anil K. Nair3

Departments of Obstetrics and Gynecology and Biological Chemistry,3 University of Michigan Medical School, Ann Arbor, Michigan 48109


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 REFERENCES
 
The LH/hCG receptor, a member of the G protein coupled receptor family mediates the cellular actions of LH in the ovary. A considerable amount of information regarding its structure, mechanism of activation, and regulation of expression has emerged in recent years. Here we provide a brief overview of the current information on the structural organization of the receptor and the mechanism of receptor mediated signaling as well as an in-depth discussion on recent developments pertaining to the regulation of receptor expression. Specifically, we describe studies from our laboratory showing that the posttranscriptional regulation of the receptor involves an LH/hCG receptor mRNA-binding protein. We also propose a model to explain the loss of steady-state LH/hCG receptor mRNA levels during receptor down-regulation.

human chorionic gonadotropin, luteinizing hormone, mechanisms of hormone action


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
REFERENCES
 
Studies on ovarian LH receptor were initiated approximately 30 yr ago, soon after techniques were developed to tag radioactive iodine onto the tyrosine residues of hCG, which, along with LH, comprise the two ligands that bind the LH/hCG receptor with high affinity. Early studies utilizing superovulated ovaries from rat and cow corpus luteum established the basic characteristics of the LH/hCG receptor with respect to its expression in target tissues, high binding affinity for ligand, limited binding capacity, binding specificity for LH or hCG, localization in the plasma membrane, inducibility by other proteins and hormones, and the ability to mediate the production of cyclic AMP in target cells [1–10]. The phenomena of transient loss of second-messenger production (desensitization) and loss of cell surface receptors (down-regulation) in response to pharmacological doses of the ligand were also described using various paradigms [8]. Attempts to purify the receptor from superovulated rat and porcine ovaries by different laboratories led to its isolation, amino terminal analysis, and subsequent cloning [9]. The cloning of the LH/hCG receptor permitted in-depth studies on its function, regulation, and structure/function relationships. Because a more exhaustive review has appeared recently on the last aspect of the LH/hCG receptor [11], we will provide only a general overview of the structural aspect and present a more comprehensive discussion on intriguing developments related to the regulation of receptor expression.

LH/hCG Receptor Structure

The LH/hCG receptor was initially cloned from rat [10] and porcine ovaries [9]. Since then, partial or complete sequences have been cloned from a number of sources, including human [12, 13; reviewed in 14, 15]. The rat LH/hCG receptor cDNA indicates that the receptor has 674 amino acid residues. The amino acid sequence suggests topological identity of the receptor to other G protein coupled receptors (GPCRs) belonging to the rhodopsin/ß2-adrenergic receptor-like family A of GPCRs. The predicted topology of the receptor indicates an extracellular domain of 340 amino acid residues, seven transmembrane spanning {alpha}-helices, intracellular and extracellular loops interconnecting the helices, and a short intracellular carboxyl terminal domain [9, 10]. The sequence of the human LH/hCG receptor is very similar to the rat receptor and consists of 675 amino acids and shares with the rat receptor approximately 90% amino acid identity in the predicted extracellular domain, about 92% identity in the transmembrane domain, and about 70% identity in the intracellular tail [11] .

The LH/hCG receptor is palmitoylated on two cysteine residues in the C-terminal tail [16, 17]. Receptor palmitoylation is believed to provide two anchoring sites for the cytosolic tail onto the plasma membrane [18]. Although abrogation of the palmitoylation sites does not reduce the ability of the receptor to bind ligand or mediate activation of adenylate cyclase or inositol phosphate breakdown [17, 19], the absence of palmitoylation increases the hCG-induced internalization of the receptor [17]. Interestingly, the constitutively active LH/hCG receptor (D556G) does not undergo palmitoylation to the same degree as the wild-type receptor [20]. Taken together with the fact that constitutively active receptors have a tendency to undergo more rapid internalization [21], it is reasonable to speculate that the wild-type receptor, after binding hormone, might undergo depalmitoylation to facilitate its internalization. Interestingly, studies on a number of GPCRs have shown dynamic regulation of receptor palmitoylation state by ligand binding (for review see [22]). Additional studies will be needed to determine whether the LH/hCG receptor undergoes such a phenomenon.

The intracellular tail portion of the rat receptor has been shown to undergo hCG-induced phosphorylation on four serine residues carboxy-terminal to the palmitoylation sites [23]. The role of phosphorylation in receptor function is controversial [11]. Although Wang et al. [24] have shown that hCG-induced rat LH/hCG receptor phosphorylation regulates receptor desensitization, studies by Lamm and Hunzicker-Dunn [25] have shown that hCG-induced phosphorylation of the porcine LH/hCG receptor is not required for agonist-induced desensitization.

LH/hCG Receptor Activation

GPCRs are believed to be stabilized by an extensive interhelical hydrogen-bonding network that renders the receptor incapable of activating cognate G protein. The transformation of the receptor to a state at which it can activate cognate G protein is promoted by disruption of these interactions (for review see [26]). For example, a naturally occurring substitution of a single aspartic acid residue with glycine in the sixth transmembrane (TM) helix of the LH/hCG receptor results in constitutive activation, presumably through a disruption of a hydrogen bond between position 556 and 593 in TM helix 7 [27–30]. A number of other point mutations have also been reported to produce constitutive activation of the LH/hCG receptor (for review see [31]). Additional laboratory-induced mutations have been characterized that are also believed to disrupt interactions between polar side chains of the TM helices [30, 32]. These studies in conjunction with LH/hCG receptor modeling suggest that TM helices 3, 6, and 7 play important roles in the receptor activation process [30]. Our laboratory has recently reported that the conserved serine residue 431 in the third TM domain is important for stabilization of the hCG-induced active state of the receptor [33]. A rhodopsin-based homology model of the LH/hCG receptor TM helices in conjunction with studies from other laboratories suggested that S431 might form a hydrogen-bonding interaction with N593 in TM7 to stabilize the hCG-induced active state. A recent study by Angelova et al. [30] involving mutagenesis and homology modeling of the LH/hCG receptor has given new insight into the possible active state conformations of constitutively active LH/hCG receptor mutants in the absence of hormone. Thus, homology based modeling of the TM helices coupled with mutational studies continues to provide insight into the possible structures of the inactive and active states of the LH/hCG receptor as well as the mechanism of receptor activation [34].

LH/hCG Receptor Signaling

The primary targets of LH are the follicles and corpus luteum in the ovary and the Leydig cells of the testis. Interestingly, expression of LH/hCG receptor mRNA has also been documented in neuronal tissue, breast cancer cell lines, and thyroid and adrenocortical cells as well as in a variety of other male and female accessory reproductive tissues [35]. LH/hCG receptor expressed in target tissues is known to respond to a physiological concentration of LH or an equivalent concentration of hCG by mediating an increase in the intracellular concentration of cyclic AMP [36]. At superphysiological concentrations, LH/hCG has been shown to stimulate phospholipase C, leading to inositol phosphate breakdown and the consequent production of inositol trisphosphate (IP3) and diacylglycerol (DAG) [37, 38]. IP3 is a stimulator of calcium mobilization [39], whereas DAG is a potent stimulator of protein kinase C [40]. Although the physiological role of LH/hCG-promoted cAMP production is well documented, the physiological state in which signaling through the phosphoinositide cascade is functional is not well understood [11]. The LH/hCG receptor has also been shown to mediate activation of the mitogen-activated protein kinase (MAPK) [41, 42] and Janus kinase-signaling pathways [43]. It has been suggested that LH-promoted MAPK stimulation may result in the desensitization of LH-stimulated steroidogenesis in granulosa cells [44].

LH/hCG Receptor Genomic Organization and mRNA Transcripts

The rat LH/hCG receptor gene contains more than 70 kb and consists of 11 exons. All but the carboxyl terminal 47 amino acid residues of the extracellular domain are encoded by exons 1–10, whereas exon 11 encodes for the remainder of the receptor [45]. Four rat LH/hCG receptor transcripts of 6.7, 4.4, 2.6, and 1.8 kb in length have been identified in ovarian tissue [10]. Studies conducted in our laboratory have shown that the 6.7-kb transcript is the most abundant form found in rat ovary and is an extension of the 4.4-kb transcript in the 3' untranslated region [46]. In fact, all four transcripts appear to be derived from the same cDNA. We found that all four transcripts are coordinately regulated in the rat ovary. Additionally, we identified cis-acting elements in the 3' untranslated region that confer LH/hCG receptor mRNA instability and consequently may regulate receptor mRNA expression under different physiological conditions [47, 48].

Regulation of LH/hCG Receptor Expression

The orderly progression of FSH and LH release plays a crucial role in follicle maturation and ovulation as well as in the formation and maintenance of the corpus luteum. LH/hCG receptors appear in the later stages of follicular development, thereby suggesting that FSH has a permissive role in the action of LH. In fact, early studies showed that large antral porcine follicles had higher levels of LH/hCG receptor than small and medium-sized follicles. Later studies revealed that pretreatment of immature rats with FSH caused a dramatic increase in the ability of granulosa cells to bind LH or hCG [5]. The expression of LH/hCG receptor increases as the follicles mature to become graafian follicles. The preovulatory surge of LH causes a transient desensitization of LH response and down-regulation of LH/hCG receptor expression. As the corpus luteum develops, the LH/hCG receptor reappears and the functional response is reinstated. In corpus luteum derived from hormonally induced superovulated rat ovary, receptor expression increases and reaches maximal levels by Day 5–8 post hCG injection. The receptor expression then shows a decline coincident with the regression of the corpus luteum [49–52].

As mentioned above, following the preovulatory surge, the ovary responds with a transient loss of responsiveness to LH. This is achieved by temporarily uncoupling the receptor from Gs and, as a consequence, inhibiting the ability of the receptor to mediate cyclic AMP production. This process is referred to as desensitization and provides a temporary reprieve for the cell to reset the metabolic machinery to respond to the next wave of hormonal stimulation. LH/hCG cell surface receptor also undergoes down-regulation to prevent the ovary from repeated stimulation. One factor that might contribute to this phenomenon is endocytosis of the receptor following hormone binding and the subsequent targeting of the hormone-receptor complex to the lysosomes [11]. Our laboratory identified and extensively characterized a mechanism occurring at the LH/hCG receptor mRNA level that contributes to the down-regulation of the LH/hCG receptor. Specifically, we found that all four LH/hCG receptor mRNA transcripts show a dramatic decline in response to a pharmacological dose of hCG [49–53] (Fig. 1). This finding was unexpected because it would be predicted that down-regulation is a consequence of increased receptor endocytosis from the cell surface rather than a change in the steady-state levels of receptor mRNA. Interestingly, similar findings were also reported by Segaloff et al. [53], who showed that hCG or cAMP analog treatment caused the loss of all LH/hCG receptor mRNA transcripts under in vitro conditions. Lapolt et al. [50] reported similar results using ovarian tissues showing that the loss of LH/hCG receptor mRNA occurs following the preovulatory LH surge.



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  		FIG. 1. Northern blot hydridization analysis of steady-state levels of LH/hCG receptor mRNA during hCG induced LH/hCG receptor down-regulation. Total RNA was isolated from the ovaries of saline-injected or hCG-injected pseudopregnant rats. Sixty micrograms of RNA was loaded onto each lane. Northern blot analysis was performed using radiolabeled cDNA corresponding to the LH/hCG receptor carboxy terminus and a portion of the 3' untranslated region (nucleotides 1936–2682) (modified from Kash and Menon [61], Fig. 1A; with permission from J Biol Chem)

The changes in the steady-state levels of LH/hCG receptor mRNA could result from either a decreased rate of receptor gene transcription and/or an increase in the rate of receptor mRNA degradation. Studies were carried out to distinguish between these two possibilities by measuring the transcription rate. Surprisingly, the results showed that the overall rate of transcription was increased following addition of hormone, probably because of increased cAMP produced in response to initial hCG stimulation. From this we concluded that the loss of steady-state levels of LH/hCG receptor mRNA in the hCG-induced down-regulated state is not the result of transcriptional arrest but is most likely due to a posttranscriptional mechanism. Further studies using rat luteal cells in a transcription arrested state showed that the decay rate of LH/hCG receptor mRNA in the down-regulated state was markedly increased [49]. Taken together these results clearly showed that the decrease in steady-state mRNA levels was due to increased degradation of the receptor mRNA as opposed to a decreased rate of transcription [49].

Our findings are in agreement with other studies showing that the steady-state levels of protein expression can be regulated at the posttranscriptional level by increasing the rate of mRNA degradation [54]. For example, the expression of mRNAs for c-fos, c-myc, and the ß2 adrenergic receptor is controlled, at least partially, at the level of mRNA degradation [55–58]. There are several other examples in which mRNA expression is regulated at the posttranscriptional level. In the majority of these cases, the change in the stability of a particular mRNA appears to result from the binding of specific proteins to defined sequences and/or structures in the target mRNA. The protein recognition sites are located in different regions of the mRNAs in different systems. For example, the ferritin mRNA sequence recognized by a stability altering RNA-binding protein is located in the 5' untranslated region. In contrast, the recognition sites have been documented to be in the coding region for ß-tubulin and in the 3' untranslated region for the ß2 adrenergic receptor and granulocyte-macrophage–colony-stimulating factor (GM-CSF). Some mRNAs also contain recognition sites in both the coding region and 3' untranslated region, as in the cases of c-fos and c-myc [58–60].

LH/hCG Receptor mRNA-Binding Protein: A Potential Trans-Acting Regulator

We undertook a study to determine whether specific mRNA-binding proteins are responsible for regulating the stability of LH/hCG receptor mRNA during down-regulation [61]. To answer this question, we developed an RNA electrophoretic gel mobility shift assay (REMSA). This assay involves radiolabeling LH/hCG receptor mRNA with [{alpha}-32P]UTP followed by incubation with a 100 000 x g supernatant (S100) fraction of an ovarian homogenate prepared from hCG-induced down-regulated ovaries. The RNA/protein complexes resulting from the incubation were separated from unbound RNA and proteins by electrophoresis on native acrylamide gels followed by detection of the complexes through autoradiography. The S100 fractions from pseudopregnant rats incubated with the radioactive mRNA resulted in the formation of a ribonucleoprotein (RNP) complex approximately 50 kDa in size. The intensity of the RNP complex in the down-regulated group was greater than in the control group. The formation of the RNP complex was tissue specific because nontarget tissues did not show complex formation [61]. We designated the protein component of the complex as the LH/hCG receptor mRNA-binding protein (LRBP).

The relationship between the steady-state levels of LH/hCG receptor mRNA expression and RNA-binding activity of LRBP was tested under conditions that represent different physiological states in the ovary [62]. When eCG-primed rats were treated with hCG to mimic the preovulatory LH surge, the expression of LH/hCG receptor mRNA transcripts showed a decline, whereas RNA-binding activity of LRBP increased (Fig. 2). The reciprocal relationship between LH/hCG receptor mRNA expression and LRBP activity was also seen during the lifespan of the corpus luteum [62]. Additionally, when LH/hCG receptor mRNA expression is down-regulated in response to chronic elevation of cAMP, the LH/hCG receptor mRNA-binding activity of LRBP was found to increase [63].



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  		FIG. 2. LH/hCG receptor mRNA expression and LRBP-binding activity during eCG (label shows "_PMSG_") and hCG induced down-regulation of LH/hCG receptor expression. Twenty-one-day-old rats were injected with eCG at 0 h and ovaries were collected immediately or 56 h post injection. The hCG was administered 56 h post eCG injection and ovaries were collected at 6, 12, 24, 48, and 72 h thereafter. REMSA was performed for all time points using 50 µg of protein isolated from ovarian S100 extracts and radiolabeled LH/hCG receptor (LHR) mRNA (C). LH/hCG receptor mRNA levels were obtained by Northern blot analysis (A). The 6.7-kb LH/hCG receptor mRNA transcript and REMSA bands were quantitated by densitometry (D). The Northern blot was normalized using 18S rRNA (B) (modified from Nair et al. [62], Fig. 5; with permission from J Biol Chem)

We partially purified this protein from the S100 fraction by standard protein purification procedures that involved ammonium sulfate precipitation followed by cation exchange chromatography. The partially purified protein was used to determine the region of the LH/hCG receptor mRNA that interacts with LRBP by incubating the protein preparation with truncated LH/hCG receptor mRNA followed by hydroxyl radical footprinting of the resultant complex [64]. The contact site was found to be located between nucleotides 203 and 220 of the receptor open reading frame and comprised of a bipartite polypyrimidine sequence (5'-UCUC-X7-UCUCCCU-3'). REMSA competition studies showed that homopolymers of (rC) were effective RNA-binding competitors, whereas poly (rA), poly (rG), or poly (rU) were not. Mutagenesis of cytidine residues within the predicted LRBP-binding site demonstrated that all cytidines in the bipartite sequence contributed to the binding specificity.

The role of LRBP as a regulator of the LH/hCG receptor mRNA expression was determined by measuring the rate of in vitro decay of LH/hCG receptor mRNA incubated in the absence or presence of a partially purified preparation of LRBP [62]. The addition of this protein increased the rate of LH/hCG receptor mRNA decay as compared with the control. This provided direct experimental evidence that LRBP causes accelerated degradation of LH/hCG receptor mRNA. These studies provide compelling evidence that LRBP is a potential trans-acting regulator of LH/hCG receptor mRNA expression. More recently this protein was purified to electrophoretic homogeneity, and its identity was established through N-terminal sequencing and MALDI/MS analysis. The protein was identified as mevalonate kinase, a member of the galactokinase, homoserine kinase, mevalonate kinase, and phosphomevalonate kinase (GHMP) kinase family of proteins that contains an unusual left-handed ß-{alpha}-ß motif named the ribosomal protein S5 domain 2-like fold [65–67 and unpublished results]. A similar fold has been found in elongation factor G, ribonuclease P, and other RNA/DNA-binding proteins [66]. Thus, because of the presence of this structural motif among this family of kinases as well as in some nucleic acid-binding proteins, we suggest that the ß-{alpha}-ß loop of mevalonate kinase could be the primary site of interaction with LH/hCG receptor mRNA. Although little is known regarding the role of this family of kinases in the regulation of reproductive function, it is interesting to note that a new member of the GHMP kinase family, XOL-1, has been implicated as a mediator of sexual differentiation in Caenorhabditis elegans [67]. Interestingly, mevalonate kinase is an enzyme that is involved in cholesterol biosynthesis and thus can have an effect on steroidogenesis in the ovary. This suggests the intriguing possibility that mevalonate kinase is a direct link between the regulation of the steroidogenic pathway and control of LH/hCG receptor mRNA expression.

Based on our observations, we present a model (Fig. 3) that shows a mechanism of down-regulation of the LH/hCG receptor during the ovarian cycle. Specifically, the preovulatory LH surge or a pharmacological dose of LH or hCG causes an increase in cellular cAMP levels and steroidogenesis. The cell then pauses in its responsiveness by transiently shutting off a number of metabolic processes that are required for increased steroidogenesis. One essential mechanism through which the cell achieves this regulation is by down-regulation of the LH/hCG receptor through a posttranscriptional mechanism. LRBP participates in this process by binding LH/hCG receptor mRNA and targeting it to degradative machinery consisting of exo- and/or endonucleases. There are a number of questions that remain unanswered with respect to our model. Among these are: 1) does LRBP needs to be activated by a posttranslational modification such as phosphorylation to bind LH/hCG receptor mRNA? and 2) what is the precise mechanism through which LRBP accelerates degradation of LH/hCG receptor mRNA? Further studies are clearly needed to address these important questions.



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  		FIG. 3. LH/hCG receptor mRNA regulation: a model. Binding of LH/hCG to LH/hCG receptor (LHR) causes an increase in intracellular cAMP levels. During the preovulatory LH surge or in response to a pharmacological dose of hCG, the increase in cAMP induces LRBP synthesis and/or activation (LRBP[A]) presumably through stimulation of protein kinase A. These events promote increased LRBP binding to LH/hCG receptor mRNA. The binding event targets the mRNA for degradation, thereby down-regulating LH/hCG receptor expression


   FOOTNOTES
 
1 Supported by National Institutes of Health Grant HD 06656. Back

2 Correspondence: K.M.J. Menon, 6428 Medical Science I, 1301 Catherine St., Ann Arbor, MI 48109-0617. FAX: 734 936 8617; kmjmenon{at}umich.edu Back

Received: 20 October 2003.

First decision: 8 November 2003.

Accepted: 25 November 2003.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 REFERENCES
 

  1. Gospodarowicz D. Properties of the luteinizing hormone receptor of isolated bovine corpus luteum plasma membranes. J Biol Chem 1973 248:5042-5049[Abstract/Free Full Text]
  2. Menon KMJ, Kiburz J. Isolation of plasma membranes from bovine corpus luteum possessing adenylate cyclase, 125I-hCG binding and Na-K-ATPase activities. Biochem Biophys Res Commun 1974 56:363-371[CrossRef][Medline]
  3. Rajaniemi HJ, Hirshfield AN, Midgley AR Jr. Gonadotropin receptors in rat ovarian tissue. I. Localization of LH binding sites by fractionation of subcellular organelles. Endocrinology 1974 95:579-588[Medline]
  4. Han SS, Rajaniemi HJ, Cho MI, Hirshfield AN, Midgley AR Jr. Gonadotropin receptors in rat ovarian tissue. II. Subcellular localization of LH binding sites by electron microscopic radioautography. Endocrinology 1974 95:589-598[Medline]
  5. Zeleznik AJ, Midgley AR Jr, Reichert LE Jr. Granulosa cell maturation in the rat: increased binding of human chorionic gonadotropin following treatment with follicle-stimulating hormone in vivo. Endocrinology 1974 95:818-825[Medline]
  6. Azhar S, Menon KMJ. Gonadotropin receptors in plasma membranes of bovine corpus luteum. I. Effect of phospholipases on the binding of 125I-choriogonadotropin by membrane-associated and solubilized receptors. J Biol Chem 1976 251:7398-7404[Abstract/Free Full Text]
  7. Azhar S, Hajra AK, Menon KMJ. Gonadotropin receptors in plasma membranes of bovine corpus luteum II. Role of membrane phospholipids. J Biol Chem 1976 251:7405-7412[Abstract/Free Full Text]
  8. Conti M, Harwood JP, Hsueh AJ, Dufau ML, Catt KJ. Gonadotropin-induced loss of hormone receptors and desensitization of adenylate cyclase in the ovary. J Biol Chem 1976 251:7729-7731[Abstract/Free Full Text]
  9. Loosfelt H, Misrahi M, Atger M, Salesse R, Vu Hai-Luu Thi MT, Jolivet A, Guiochon-Mantel A, Sar S, Jallal B, Garnier J, Milgrom E. Cloning and sequencing of porcine LH-hCG receptor cDNA: variants lacking transmembrane domain. Science 1989 245:525-528[Abstract/Free Full Text]
  10. McFarland KC, Sprengel R, Phillips HS, Kohler M, Rosemblit N, Nikolics K, Segaloff DL, Seeburg PH. Lutropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 1989 245:494-499[Abstract/Free Full Text]
  11. Ascoli M, Fanelli F, Segaloff DL. The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 2002 23:141-174[Abstract/Free Full Text]
  12. Minegishi T, Nakamura K, Takakura Y, Miyamoto K, Hasegawa Y, Ibuki Y, Igarashi M, Minegishi T. Cloning and sequencing of human LH/hCG receptor cDNA. Biochem Biophys Res Commun 1990 172:1049-1054[CrossRef][Medline]
  13. Jia XC, Oikawa M, Bo M, Tanaka T, Ny T, Boime I, Hsueh AJ. Expression of human luteinizing hormone (LH) receptor: interaction with LH and chorionic gonadotropin from human but not equine, rat, and ovine species. Mol Endocrinol 1991 5:759-768[CrossRef][Medline]
  14. Segaloff DL, Ascoli M. The lutropin/choriogonadotropin receptor ... 4 years later. Endocr Rev 1993 14:324-347[CrossRef][Medline]
  15. Segaloff DL, Ascoli M. The gonadotrophin receptors: insights from the cloning of their cDNAs. Oxf Rev Reprod Biol 1992 14:141-168[Medline]
  16. Zhu H, Wang H, Ascoli M. The lutropin/choriogonadotropin receptor is palmitoylated at intracellular cysteine residues. Mol Endocrinol 1995 9:141-150[Abstract]
  17. Kawate N, Menon KMJ. Palmitoylation of luteinizing hormone/human choriogonadotropin receptors in transfected cells. Abolition of palmitoylation by mutation of Cys-621 and Cys-622 residues in the cytoplasmic tail increases ligand-induced internalization of the receptor. J Biol Chem 1994 269:30651-30658[Abstract/Free Full Text]
  18. Moench SJ, Moreland J, Stewart DH, Dewey TG. Fluorescence studies of the location and membrane accessibility of the palmitoylation sites of rhodopsin. Biochemistry 1994 33:5791-5796[CrossRef][Medline]
  19. Munshi UM, Peegel H, Menon KMJ. Palmitoylation of the luteinizing hormone/human chorionic gonadotropin receptor regulates receptor interaction with the arrestin-mediated internalization pathway. Eur J Biochem 2001 268:1631-1639[Medline]
  20. Bradbury FA, Kawate N, Foster CM, Menon KMJ. Post-translational processing in the Golgi plays a critical role in the trafficking of the luteinizing hormone/human chorionic gonadotropin receptor to the cell surface. J Biol Chem 1997 272:5921-5926[Abstract/Free Full Text]
  21. Bradbury FA, Menon KMJ. Evidence that constitutively active luteinizing hormone/human chorionic gonadotropin receptors are rapidly internalized. Biochemistry 1999 38:8703-8712[CrossRef][Medline]
  22. Qanbar R, Bouvier M. Role of palmitoylation/depalmitoylation reactions in G-protein-coupled receptor function. Pharmacol Ther 2003 97:1-33[CrossRef][Medline]
  23. Hipkin RW, Wang Z, Ascoli M. Human chorionic gonadotropin (CG)- and phorbol ester-stimulated phosphorylation of the luteinizing hormone/CG receptor maps to serines 635, 639, 649, and 652 in the C-terminal cytoplasmic tail. Mol Endocrinol 1995 9:151-158[Abstract]
  24. Wang Z, Liu X, Ascoli M. Phosphorylation of the lutropin/choriogonadotropin receptor facilitates uncoupling of the receptor from adenylyl cyclase and endocytosis of the bound hormone. Mol Endocrinol 1997 11:183-192[Abstract/Free Full Text]
  25. Lamm ML, Hunzicker-Dunn M. Phosphorylation-independent desensitization of the luteinizing hormone/chorionic gonadotropin receptor in porcine follicular membranes. Mol Endocrinol 1994 8:1537-1546[Abstract]
  26. Gether U, Asmar F, Meinild AK, Rasmussen SG. Structural basis for activation of G-protein-coupled receptors. Pharmacol Toxicol 2002 91:304-312[CrossRef][Medline]
  27. Kremer H, Mariman E, Otten BJ, Moll Jr GW, Stoelinga GB, Wit JM, Jansen M, Drop SL, Faas B, Ropers HH, Brunner HG. Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty. Hum Mol Genet 1993 2:1779-1783[Abstract/Free Full Text]
  28. Shenker A, Laue L, Kosugi S, Merendino JJ Jr, Minegishi T, Cutler GB Jr. A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. Nature 1993 365:652-654[CrossRef][Medline]
  29. Kawate N, Kletter GB, Wilson BE, Netzloff ML, Menon KMJ. Identification of constitutively activating mutation of the luteinising hormone receptor in a family with male limited gonadotrophin independent precocious puberty (testitoxicosis). J Med Genet 1995 32:553-554[Abstract/Free Full Text]
  30. Angelova K, Fanelli F, Puett D. A model for constitutive lutropin receptor activation based on molecular simulation and engineered mutations in transmembrane helices 6 and 7. J Biol Chem 2002 277:32202-32213[Abstract/Free Full Text]
  31. Shenker A. Activating mutations of the lutropin choriogonadotropin receptor in precocious puberty. Receptors Channels 2002 8:3-18[CrossRef][Medline]
  32. Angelova K, Narayan P, Simon JP, Puett D. Functional role of transmembrane helix 7 in the activation of the heptahelical lutropin receptor. Mol Endocrinol 2000 14:459-471[Abstract/Free Full Text]
  33. Munshi UM, Pogozheva ID, Menon KMJ. Highly conserved serine in the third transmembrane helix of the luteinizing hormone/human chorionic gonadotropin receptor regulates receptor activation. Biochemistry 2003 42:3708-3715[CrossRef][Medline]
  34. Fanelli F, Puett D. Structural aspects of luteinizing hormone receptor: information from molecular modeling and mutagenesis. Endocrine 2002 18:285-293[CrossRef][Medline]
  35. Rao CV. An overview of the past, present, and future of nongonadal LH/hCG actions in reproductive biology and medicine. Semin Reprod Med 2001 19:7-17[CrossRef][Medline]
  36. Menon KMJ, Gunaga KP. Role of cyclic AMP in reproductive processes. Fertil Steril 1974 25:732-750[Medline]
  37. Davis JS, West LA, Farese RV. Effects of luteinizing hormone on phosphoinositide metabolism in rat granulosa cells. J Biol Chem 1984 259:15028-15034[Abstract/Free Full Text]
  38. Gudermann T, Birnbaumer M, Birnbaumer L. Evidence for dual coupling of the murine luteinizing hormone receptor to adenylyl cyclase and phosphoinositide breakdown and Ca2+ mobilization. Studies with the cloned murine luteinizing hormone receptor expressed in L cells. J Biol Chem 1992 267:4479-4488[Abstract/Free Full Text]
  39. Berridge MJ, Irvine RF. Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 1984 312:315-321[CrossRef][Medline]
  40. Nishizuka Y. The role of protein kinase C in cell surface signal transduction and tumour promotion. Nature 1984 308:693-698[CrossRef][Medline]
  41. Salvador LM, Maizels E, Hales DB, Miyamoto E, Yamamoto H, Hunzicker-Dunn M. Acute signaling by the LH receptor is independent of protein kinase C activation. Endocrinology 2002 143:2986-2994[Abstract/Free Full Text]
  42. Srisuparp S, Strakova Z, Brudney A, Mukherjee S, Reierstad S, Hunzicker-Dunn M, Fazleabas AT. Signal transduction pathways activated by chorionic gonadotropin in the primate endometrial epithelial cells. Biol Reprod 2003 68:457-464[Abstract/Free Full Text]
  43. Carvalho CR, Carvalheira JB, Lima MH, Zimmerman SF, Caperuto LC, Amanso A, Gasparetti AL, Meneghetti V, Zimmerman LF, Velloso LA, Saad MJ. Novel signal transduction pathway for luteinizing hormone and its interaction with insulin: activation of Janus kinase/signal transducer and activator of transcription and phosphoinositol 3-kinase/Akt pathways. Endocrinology 2003 144:638-647[Abstract/Free Full Text]
  44. Amsterdam A, Hanoch T, Dantes A, Tajima K, Strauss JF, Seger R. Mechanisms of gonadotropin desensitization. Mol Cell Endocrinol 2002 187:69-74[CrossRef][Medline]
  45. Tsai-Morris C, Buczko E, Wang W, Xie X, Dufau M. Structural organization of the rat luteinizing hormone (LH) receptor gene. J Biol Chem 1991 266:11355-11359[Abstract/Free Full Text]
  46. Lu DL, Menon KMJ. Molecular cloning of a novel luteinizing-hormone/human-chorionic-gonadotropin-receptor cDNA: identification of a long 3' untranslated region and cDNA sequence of the major transcript in rat ovary. Eur J Biochem 1994 222:753-760[Medline]
  47. Lu DL, Menon KMJ. 3' Untranslated region-mediated regulation of luteinizing hormone/human chorionic gonadotropin receptor expression. Biochemistry 1996 35:12347-12353[CrossRef][Medline]
  48. Nair AK, Menon KMJ. Regulatory role of the 3' untranslated region of luteinizing hormone receptor: effect on mRNA stability. FEBS Lett 2000 471:39-44[CrossRef][Medline]
  49. Lu DL, Peegel H, Mosier SM, Menon KMJ. Loss of lutropin/human choriogonadotropin receptor messenger ribonucleic acid during ligand-induced down-regulation occurs post-transcriptionally. Endocrinology 1993 132:235-240[Abstract]
  50. Lapolt PS, Oikawa M, Jia XC, Dargan C, Hsueh AJ. Gonadotropin-induced up- and down-regulation of rat ovarian LH receptor message levels during follicular growth, ovulation and luteinization. Endocrinology 1990 126:3277-3279[Abstract]
  51. Hoffman YM, Peegel H, Sprock MJ, Zhang QY, Menon KMJ. Evidence that human chorionic gonadotropin/luteinizing hormone receptor down-regulation involves decreased levels of receptor messenger ribonucleic acid. Endocrinology 1991 128:388-393[Abstract]
  52. Peegel H, Randolph J Jr, Midgley AR Jr, Menon KMJ. In situ hybridization of luteinizing hormone/human chorionic gonadotropin receptor messenger ribonucleic acid during hormone-induced down-regulation and the subsequent recovery in rat corpus luteum. Endocrinology 1994 135:1044-1051[Abstract]
  53. Segaloff DL, Wang HY, Richards JS. Hormonal regulation of luteinizing hormone/chorionic gonadotropin receptor mRNA in rat ovarian cells during follicular development and luteinization. Mol Endocrinol 1990 4:1856-1865[CrossRef][Medline]
  54. Ross J. mRNA stability in mammalian cells. Microbiol Rev 1995 59:423-450[Abstract/Free Full Text]
  55. Bernstein PL, Herrick DJ, Prokipcak RD, Ross J. Control of c-myc mRNA half-life in vitro by a protein capable of binding to a coding region stability determinant. Genes Dev 1992 6:642-654[Abstract/Free Full Text]
  56. Port JD, Huang LY, Malbon CC. ß-Adrenergic agonists that down-regulate receptor mRNA up-regulate a Mr 35000 protein(s) that selectively binds to ß-adrenergic receptor mRNAs. J Biol Chem 1992 267:24103-24108[Abstract/Free Full Text]
  57. Sachs AB. Messenger RNA degradation in eukaryotes. Cell 1993 74:413-421[CrossRef][Medline]
  58. Shyu AB, Greenberg ME, Belasco JG. The c-fos transcript is targeted for rapid decay by two distinct mRNA degradation pathways. Genes Dev 1989 3:60-72[Abstract/Free Full Text]
  59. Herrick DJ, Ross J. The half-life of c-myc mRNA in growing and serum-stimulated cells: influence of the coding and 3' untranslated regions and role of ribosome translocation. Mol Cell Biol 1994 14:2119-2128[Abstract/Free Full Text]
  60. Shyu AB, Belasco JG, Greenberg ME. Two distinct destabilizing elements in the c-fos message trigger deadenylation as a first step in rapid mRNA decay. Genes Dev 1991 5:221-231[Abstract/Free Full Text]
  61. Kash JC, Menon KMJ. Identification of a hormonally regulated luteinizing hormone/human chorionic gonadotropin receptor mRNA binding protein. Increased mRNA binding during receptor down-regulation. J Biol Chem 1998 273:10658-10664[Abstract/Free Full Text]
  62. Nair AK, Kash JC, Peegel H, Menon KMJ. Post-transcriptional regulation of luteinizing hormone receptor mRNA in the ovary by a novel mRNA-binding protein. J Biol Chem 2002 277:21468-21473[Abstract/Free Full Text]
  63. Towns R, Nair AK, Peegel H, Menon KMJ. A novel mechanism for the modulation of LH receptor mRNA expression in the ovary. In: Program of the 36th annual meeting of the Society for the Study of Reproduction; 2003; Cincinnati, OH. Abstract 448
  64. Kash JC, Menon KMJ. Sequence-specific binding of a hormonally regulated mRNA binding protein to cytidine-rich sequences in the lutropin receptor open reading frame. Biochemistry 1999 38:16889-16897[CrossRef][Medline]
  65. Wimberly BT, Brodersen DE, Clemons WM Jr, Morgan-Warren RJ, Carter AP, Vonrhein C, Hartsch T, Ramakrishnan V. Structure of the 30S ribosomal subunit. Nature 2000 407:327-339[CrossRef][Medline]
  66. Zhou T, Daugherty M, Grishin NV, Osterman AL, Zhang H. Structure and mechanism of homoserine kinase: prototype for the GHMP kinase superfamily. Structure Fold Des 2000 8:1247-1257[Medline]
  67. Luz JG, Hassig CA, Pickle C, Godzik A, Meyer BJ, Wilson IA. XOL-1, primary determinant of sexual fate in C. elegans, is a GHMP kinase family member and a structural prototype for a class of developmental regulators. Genes Dev 2003 17:977-990[Abstract/Free Full Text]



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