Learning New Tricks from an Old Dog: The Processing of the Intracellular Precursor of the Luteinizing Hormone Receptor (LHR) into the Mature
http://www.100md.com
内分泌学杂志 2005年第8期
Department of Pharmacology Carver College of Medicine The University of Iowa Iowa City, Iowa 52242
Address all correspondence and requests for reprints to: Dr. Mario Ascoli, Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242. E-mail: mario-ascoli@uiowa.edu.
The cloning of the cDNAs for the rat (1) and porcine (2) LH receptor (LHR) in 1989 provided us with new experimental tools that resulted in a tremendous explosion in our knowledge of the structure and functions of the LHR as well as the closely related FSH and TSH receptors (reviewed in Refs. 3, 4, 5, 6, 7). Some of the most important recent advances in this area include 1) the discovery that naturally occurring mutations of these three receptors are responsible for some endocrine disorders (7, 8, 9); 2) the generation of FSH receptor- (10) and LHR-null mice (11, 12); and 3) the recent report of the crystal structure of a portion of the extracellular domain of the FSH receptor bound to FSH (13).
One aspect of the biology of the LHR that has remained rather mysterious is the possibility that this receptor may be widely expressed in extragonadal tissues, thus making LH and chorionic gonadotropin (CG) pleiotropic rather than gonadal-specific hormones. Although there are many reports documenting the presence of LHR transcripts and/or protein in an ever-increasing number of extragonadal tissues (reviewed in Refs. 14, 15, 16, 17), the significance of these findings remains, for the most part, poorly understood. In this issue, Apaja et al. (18) add new fuel to the fire by documenting that the maturation of the intracellular precursor of the rat (r) LHR into the mature cell-surface protein (i.e. the LHR that is exposed to circulating gonadotropins) is a regulated process. They show that the developing rodent gonads, as well as several extragonadal tissues, express only the immature form of the LHR, whereas other tissues such as the mature gonads, adult female adrenal, and the kidneys of pregnant rats express both the immature and the mature LHR. The studies of Apaja et al. (18) are particularly convincing because they studied the expression of the LHR using several experimental approaches such as expression of a LacZ reporter driven by the murine LHR promoter and nested PCR to assess the presence of LHR transcripts. Finally, affinity purification or immunoprecipitation was also used to assess the expression of different forms of the LHR protein.
Rodent and porcine ovaries and testes express at least two forms of the LHR, an 85- to 95- and a 68- to 75-kDa protein 1 (20, 21, 22, 23, 24, 25). Studies on the nature of these two forms of the LHR have been conducted mostly in mammalian cells transfected with the cDNAs for the porcine, rat, or human (h) LHR (reviewed in Ref. 4). The 85- to 95-kDa band present in transfected cells is the mature LHR located at the cell surface, as judged by surface biotinylation of intact cells and its susceptibility to degradation by surface proteolysis, neuraminidase and PGNase F (22, 26, 27). In contrast, the 85- to 95-kDa LHR is not susceptible to EndoH, a glycosidase that removes the type of carbohydrate side chains associated with immature glycoproteins that reside in the endoplasmic reticulum (21, 22, 28, 29). Conversely, the 68- to 75-kDa appears to be located intracellularly because it is readily susceptible to EndoH digestion and it cannot be detected by surface biotinylation of intact cells (21, 22, 26, 28). This form of the LHR is also insensitive to surface proteolysis and neuraminidase digestion (22, 26, 27, 28, 29). Biosynthetic labeling of heterologous cells transfected with rLHR also revealed that the 68- to 75-kDa rLHR is a precursor of the 85- to 95-kDa rLHR (22, 29). In transfected cells, the conversion of the immature to the mature form of the rLHR is a slow and inefficient process, however, and a large proportion of the immature rLHR is never converted to the mature receptor (22, 30, 31, 32, 33). Importantly, the immature form of the rLHR can bind hCG with the same affinity as the mature rLHR (27), but the binding affinity of ovine LH for the mature rLHR is higher than its binding affinity for the rLHR precursor (34). Clearly then, although the immature rLHR has attained a conformation that permits hormone binding, this conformation is not the same as that of the mature form of the rLHR. In addition, because of its intracellular location, the immature LHR cannot come in contact with circulating gonadotropins.
In documenting the presence of the immature, but not the mature, form of the LHR in the developing rat gonads, the studies of Apaja et al. (18) are interesting because they imply that these tissues are not sensitive to gonadotropin stimulation. Their finding is in perfect agreement with the phenotype of the LHR-null mice that display no abnormalities in sexual differentiation (11, 12). In fact, an important conclusion established from the phenotype of these animals is that sexual differentiation in rodents is independent of gonadotropin actions (11, 12). This, of course, is in contrast with the need for gonadotropin action during sexual differentiation in humans. 46XY individuals who are homozygous (or compound heterozygous) for loss-of-function mutations of the LHR display various degrees of feminization of their external genitalia (8, 9). Herein lies an important difference between sexual differentiation in rodents and humans that may be related to the processing (or the regulation of the processing) of the immature to mature forms of the LHR in these two species. It is already known that at steady state the relative abundance of the mature LHR is much lower than that of the immature LHR in cells transfected with the rLHR, but the mature form of the LHR is more abundant than the immature form in cells transfected with the hLHR (reviewed in Ref. 4). If this is also true in human and rat gonadal cells then the developing human gonads are likely to be more sensitive to gonadotropins because they would express more LHR at the cell surface than do the rat gonads. From an evolutionary standpoint this would fit nicely with the presence of a gonadotropin of pregnancy (hCG) in humans but not in rodents.
The increased level of mature rLHR in the adrenals and kidneys of pregnant rats reported by Apaja et al. (18) is also interesting because it shows that the maturation of the LHR is under physiological control. Because it has already been shown that the expression of the LHR mRNA is regulated at transcriptional and posttranscriptional steps (reviewed in Ref. 35), these findings add a new layer of complexity to the different processes that are involved in the regulation of the expression of the cell-surface LHR. Moreover, because the temporal expression of the mature LHR in the pregnant adrenal and kidneys coincides with the differentiation of the fetal urogenital structures, it suggests that the ability of these two tissues to respond to gonadotropins may be involved in sexual differentiation in rodents.
Lastly, because most extragonadal tissues express only the immature LHR (18) and this form of the LHR is not exposed to the hormone, it appears that most of the extragonadal LHR expression may have little or no physiological significance. There are some tissues in which this is clearly not the case, however. Adult and developing rat nervous tissue (23) and the pregnant rat kidney and adrenal gland appear to be notable exceptions (18). The adrenal expression of the mature LHR is or particular interest because several other groups have previously reported the presence of functional LHR in the adrenals of transgenic or knockout mouse models with elevated levels of gonadotropins (36, 37, 38, 39) and in the adrenals of some women who experience Cushing’s syndrome (40, 41).
In summary, the paper by Apaja et al. (18) documents novel aspects of the developmental and physiological regulation of the processing of the LHR, and it raises the bar for future studies on the extragonadal expression of the LHR. Such studies will now have to carefully consider whether the expressed LHR protein is the mature or immature form of the receptor. In addition, these studies raise a number of questions regarding the physiological, cellular, and molecular aspects of the regulation of the processing and maturation of the LHR.
References
McFarland KC, Sprengel R, Phillips HS, Kohler M, Rosemblit N, Nikolics K, Segaloff DL, Seeburg PH 1989 Lutropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 245:494–499
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 1989 Cloning and sequencing of porcine LH-hCG receptor cDNA: variants lacking transmembrane domain. Science 245:525–528
Segaloff DL, Ascoli M 1993 The lutropin/choriogonadotropin (LH/CG) receptor... 4 years later. Endocr Rev 14:324–347
Ascoli M, Fanelli F, Segaloff DL 2002 The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23:141–174
Dias JA, Cohen BD, Lindau-Shepard B, Nechamen CA, Peterson AJ, Schmidt A 2002 Molecular, structural, and cellular biology of follitropin and follitropin receptor. Vit Horm 64:249–322
Rapoport B, Chazenbalk D, Jaume JC, McLachlan SM 1998 The thyrotropin (TSH) hormone receptor: interaction with TSH and autoantibodies. Endocr Rev 19:673–716
Vassart G, Pardo L, Costagliola S 2004 A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci 29:119–126
Latronico AC, Segaloff DL 1999 Naturally occurring mutations of the luteinizing-hormone receptor: lessons learned about reproductive physiology and G protein-coupled receptors. Am J Hum Genet 65:949–958
Themmen APN, Huhtaniemi IT 2000 Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 21:551–583
Dierich A, Sairam MR, Monaco L, Fimia GM, Gansmuller A, LeMeur M, Sassone-Corsi PS 1998 Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc Natl Acad Sci USA 95:13612–13617
Zhang F-P, Poutanen M, Wilbertz J, Huhtaniemi I 2001 Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice. Mol Endocrinol 15:172–183
Lei ZM, Mishra S, Zou W, Xu B, Foltz M, Li X, Rao CV 2001 Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene. Mol Endocrinol 15:184–200
Fan QR, Hendricson WA 2005 Structure of the human follicle-stimulating hormone in complex with its receptors. Nature 433:269–277
Rao CV 2001 An overview of the past, present, and future of non-gonadal LH/hCG actions in reproductive biology and medicine. Semin Reprod Med 19:7–17
Rao CV 1996 The beginning of a new era in reproductive biology and medicine: expression of low levels of functional luteinizing hormone hormone/human chorionic gonadotropin receptors in nongonadal tissues. J Physiol Pharmacol 47:41–53
Rao CV, Lei ZM 2002 Consequences of targeted inactivation of LH receptors. Mol Cell Endocrinol 187:57–67
Rao CV 2001 Multiple novel roles of luteinizing hormone. Fertil Steril 76:1097–1100
Apaja PM, Aatsinki JT, Rajaniemi HJ, Pet?j?-Repo UE 2005 Expression of the mature luteinizing hormone receptor in rodent urogenital and adrenal tissues is developmentally regulated at a posttranslational level. Endocrinology 146:3224–3232
Tao Y-X, Johnson NB, Segaloff DL 2004 Constitutive and agonist-dependent self-association of the cell surface human lutropin receptor. J Biol Chem 279:5904–5914
Vuhai-Luuthi MT, Jolivet A, Jallal B, Salesse R, Bidart J-M, Houllier A, Guiochon-Mantel A, Garnier J, Milgrom E 1990 Monoclonal antibodies against luteinizing hormone receptor. Immunochemical characterization of the receptor. Endocrinology 127:2090–2098
VuHai-LuuThi MT, Misrahi M, Houillier A, Jolivet A, Milgrom E 1992 Variant forms of the pig lutropin/choriogonadotropin receptor. Biochemistry 31:8377–8383
Hipkin RW, Sánchez-Yagüe J, Ascoli M 1992 Identification and characterization of a luteinizing hormone/chorionic gonadotropin (LH/CG) receptor precursor in a human kidney cell line stably transfected with the rat luteal LH/CG receptor complementary DNA. Mol Endocrinol 6:2210–2218
Apaja PM, Harju KT, Aatsinki JT, Petaja-Repo UE, Rajaniemi HJ 2004 Identification and Structural Characterization of the Neuronal Luteinizing Hormone Receptor Associated with Sensory Systems. J Biol Chem 279:1899–1906
Keinanen KP, Kellokumpu S, Rajaniemi HJ 1987 Visualization of the rat ovarian lutropin receptor by ligand blotting. Mol Cell Endocrinol 49:33–38
Keinanen KP, Kellokumpu S, Metsikko MK, Rajaniemi HJ 1987 Purification and partial characterization of rat ovarian lutropin receptor. J Biol Chem 262:7920–7926
Min L, Ascoli M 2000 Effect of activating and inactivating mutations on the phosphorylation and trafficking of the human lutropin/choriogonadotropin receptor. Mol Endocrinol 14:1797–1810
Fabritz J, Ryan S, Ascoli M 1998 Transfected cells express mostly the intracellular precursor of the lutropin/choriogonadotropin receptor but this precursor binds choriogonadotropin with high affinity. Biochemistry 37:664–672
Davis DP, Rozell TG, Liu X, Segaloff DL 1997 The six N-linked carbohydrates of the lutropin/choriogonadotropin receptor are not absolutely required for correct folding, cell surface expression, hormone binding or signal transduction. Mol Endocrinol 11:550–562
Bradbury FA, Kawate N, Foster CM, Menon KMJ 1997 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 272:5921–5926
Zhu H, Wang H, Ascoli M 1995 The lutropin/choriogonadotropin (LH/CG) receptor is palmitoylated at intracellular cysteine residues. Mol Endocrinol 9:141–150
Min K-S, Liu X, Fabritz J, Jaquette J, Abell AN, Ascoli M 1998 Mutations that induce constitutive activation and mutations that impair signal transduction modulate the basal and/or agonist-stimulated internalization of the lutropin/choriogonadotropin receptor. J Biol Chem 273:34911–34919
Li S, Liu X, Ascoli M 2000 p38JAB1 Binds to the intracellular precursor of the lutropin/choriogonadotropin receptor and promotes its degradation. J Biol Chem 275:13386–13393
Rozell TG, Davis DP, Chai Y, Segaloff DL 1998 Association of gonadotropin receptor precursors with the protein folding chaperone calnexin. Endocrinology 139:1588–1593
Abell A, Liu X, Segaloff DL 1996 Deletions of portions of the extracellular loops of the lutropin/choriogonadotropin receptor decrease the binding affinity for ovine luteinizing hormone, but not for human choriogonadotropin, by preventing the formation of mature cell surface receptor. J Biol Chem 271:4518–4527
Menon KMJ, Munshi UM, Clouser CL, Nair AK 2004 Regulation of luteinizing hormone/human chorionic gonadotropin receptor expression: a perspective. Biol Reprod 70:861–866
Kumar TR, Wang Y, Matzuk MM 1996 Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice. Endocrinology 137:4210–4216
Kananen K, Rillianawati Paukku T, Markkula M, Rainio E-M, Huhtaniemi IT 1997 Suppression of gonadotropins inhibits gonadal tumorigenesis in mice transgenic for the mouse inhibin-a subunit promoter/SV40 T-antigen fusion gene. Endocrinology 138:3521–3531
Rilianawati, Paukku T, Kero J, Zhang F-P, Rahman N, Kananen K, Huhtaniemi I 1998 Direct luteinizing hormone action triggers adrenocortical tumorigenesis in castrated mice transgenic for the murine inhibin -subunit promoter/simian virus 40 T-antigen fusion gene. Mol Cell Endocrinol 12:801–809
Kero J, Poutanen M, Zhang FP, Rahman N, McNicol AM, Nilson JH, Keri RA, Huhtaniemi IT 2000 Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J. Clin. Invest 105:633–641
Lacroix A, Hamet P, Boutin JM 1999 Leuprolide acetate therapy in luteinizing hormone-dependent Cushing’s syndrome. New Engl J Med 341:1577–1581
Lacroix A, N'Diaye N, Tremblay J, Hamet P 2001 Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocr Rev 22:75–110(Mario Ascoli)
Address all correspondence and requests for reprints to: Dr. Mario Ascoli, Department of Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242. E-mail: mario-ascoli@uiowa.edu.
The cloning of the cDNAs for the rat (1) and porcine (2) LH receptor (LHR) in 1989 provided us with new experimental tools that resulted in a tremendous explosion in our knowledge of the structure and functions of the LHR as well as the closely related FSH and TSH receptors (reviewed in Refs. 3, 4, 5, 6, 7). Some of the most important recent advances in this area include 1) the discovery that naturally occurring mutations of these three receptors are responsible for some endocrine disorders (7, 8, 9); 2) the generation of FSH receptor- (10) and LHR-null mice (11, 12); and 3) the recent report of the crystal structure of a portion of the extracellular domain of the FSH receptor bound to FSH (13).
One aspect of the biology of the LHR that has remained rather mysterious is the possibility that this receptor may be widely expressed in extragonadal tissues, thus making LH and chorionic gonadotropin (CG) pleiotropic rather than gonadal-specific hormones. Although there are many reports documenting the presence of LHR transcripts and/or protein in an ever-increasing number of extragonadal tissues (reviewed in Refs. 14, 15, 16, 17), the significance of these findings remains, for the most part, poorly understood. In this issue, Apaja et al. (18) add new fuel to the fire by documenting that the maturation of the intracellular precursor of the rat (r) LHR into the mature cell-surface protein (i.e. the LHR that is exposed to circulating gonadotropins) is a regulated process. They show that the developing rodent gonads, as well as several extragonadal tissues, express only the immature form of the LHR, whereas other tissues such as the mature gonads, adult female adrenal, and the kidneys of pregnant rats express both the immature and the mature LHR. The studies of Apaja et al. (18) are particularly convincing because they studied the expression of the LHR using several experimental approaches such as expression of a LacZ reporter driven by the murine LHR promoter and nested PCR to assess the presence of LHR transcripts. Finally, affinity purification or immunoprecipitation was also used to assess the expression of different forms of the LHR protein.
Rodent and porcine ovaries and testes express at least two forms of the LHR, an 85- to 95- and a 68- to 75-kDa protein 1 (20, 21, 22, 23, 24, 25). Studies on the nature of these two forms of the LHR have been conducted mostly in mammalian cells transfected with the cDNAs for the porcine, rat, or human (h) LHR (reviewed in Ref. 4). The 85- to 95-kDa band present in transfected cells is the mature LHR located at the cell surface, as judged by surface biotinylation of intact cells and its susceptibility to degradation by surface proteolysis, neuraminidase and PGNase F (22, 26, 27). In contrast, the 85- to 95-kDa LHR is not susceptible to EndoH, a glycosidase that removes the type of carbohydrate side chains associated with immature glycoproteins that reside in the endoplasmic reticulum (21, 22, 28, 29). Conversely, the 68- to 75-kDa appears to be located intracellularly because it is readily susceptible to EndoH digestion and it cannot be detected by surface biotinylation of intact cells (21, 22, 26, 28). This form of the LHR is also insensitive to surface proteolysis and neuraminidase digestion (22, 26, 27, 28, 29). Biosynthetic labeling of heterologous cells transfected with rLHR also revealed that the 68- to 75-kDa rLHR is a precursor of the 85- to 95-kDa rLHR (22, 29). In transfected cells, the conversion of the immature to the mature form of the rLHR is a slow and inefficient process, however, and a large proportion of the immature rLHR is never converted to the mature receptor (22, 30, 31, 32, 33). Importantly, the immature form of the rLHR can bind hCG with the same affinity as the mature rLHR (27), but the binding affinity of ovine LH for the mature rLHR is higher than its binding affinity for the rLHR precursor (34). Clearly then, although the immature rLHR has attained a conformation that permits hormone binding, this conformation is not the same as that of the mature form of the rLHR. In addition, because of its intracellular location, the immature LHR cannot come in contact with circulating gonadotropins.
In documenting the presence of the immature, but not the mature, form of the LHR in the developing rat gonads, the studies of Apaja et al. (18) are interesting because they imply that these tissues are not sensitive to gonadotropin stimulation. Their finding is in perfect agreement with the phenotype of the LHR-null mice that display no abnormalities in sexual differentiation (11, 12). In fact, an important conclusion established from the phenotype of these animals is that sexual differentiation in rodents is independent of gonadotropin actions (11, 12). This, of course, is in contrast with the need for gonadotropin action during sexual differentiation in humans. 46XY individuals who are homozygous (or compound heterozygous) for loss-of-function mutations of the LHR display various degrees of feminization of their external genitalia (8, 9). Herein lies an important difference between sexual differentiation in rodents and humans that may be related to the processing (or the regulation of the processing) of the immature to mature forms of the LHR in these two species. It is already known that at steady state the relative abundance of the mature LHR is much lower than that of the immature LHR in cells transfected with the rLHR, but the mature form of the LHR is more abundant than the immature form in cells transfected with the hLHR (reviewed in Ref. 4). If this is also true in human and rat gonadal cells then the developing human gonads are likely to be more sensitive to gonadotropins because they would express more LHR at the cell surface than do the rat gonads. From an evolutionary standpoint this would fit nicely with the presence of a gonadotropin of pregnancy (hCG) in humans but not in rodents.
The increased level of mature rLHR in the adrenals and kidneys of pregnant rats reported by Apaja et al. (18) is also interesting because it shows that the maturation of the LHR is under physiological control. Because it has already been shown that the expression of the LHR mRNA is regulated at transcriptional and posttranscriptional steps (reviewed in Ref. 35), these findings add a new layer of complexity to the different processes that are involved in the regulation of the expression of the cell-surface LHR. Moreover, because the temporal expression of the mature LHR in the pregnant adrenal and kidneys coincides with the differentiation of the fetal urogenital structures, it suggests that the ability of these two tissues to respond to gonadotropins may be involved in sexual differentiation in rodents.
Lastly, because most extragonadal tissues express only the immature LHR (18) and this form of the LHR is not exposed to the hormone, it appears that most of the extragonadal LHR expression may have little or no physiological significance. There are some tissues in which this is clearly not the case, however. Adult and developing rat nervous tissue (23) and the pregnant rat kidney and adrenal gland appear to be notable exceptions (18). The adrenal expression of the mature LHR is or particular interest because several other groups have previously reported the presence of functional LHR in the adrenals of transgenic or knockout mouse models with elevated levels of gonadotropins (36, 37, 38, 39) and in the adrenals of some women who experience Cushing’s syndrome (40, 41).
In summary, the paper by Apaja et al. (18) documents novel aspects of the developmental and physiological regulation of the processing of the LHR, and it raises the bar for future studies on the extragonadal expression of the LHR. Such studies will now have to carefully consider whether the expressed LHR protein is the mature or immature form of the receptor. In addition, these studies raise a number of questions regarding the physiological, cellular, and molecular aspects of the regulation of the processing and maturation of the LHR.
References
McFarland KC, Sprengel R, Phillips HS, Kohler M, Rosemblit N, Nikolics K, Segaloff DL, Seeburg PH 1989 Lutropin-choriogonadotropin receptor: an unusual member of the G protein-coupled receptor family. Science 245:494–499
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 1989 Cloning and sequencing of porcine LH-hCG receptor cDNA: variants lacking transmembrane domain. Science 245:525–528
Segaloff DL, Ascoli M 1993 The lutropin/choriogonadotropin (LH/CG) receptor... 4 years later. Endocr Rev 14:324–347
Ascoli M, Fanelli F, Segaloff DL 2002 The lutropin/choriogonadotropin receptor, a 2002 perspective. Endocr Rev 23:141–174
Dias JA, Cohen BD, Lindau-Shepard B, Nechamen CA, Peterson AJ, Schmidt A 2002 Molecular, structural, and cellular biology of follitropin and follitropin receptor. Vit Horm 64:249–322
Rapoport B, Chazenbalk D, Jaume JC, McLachlan SM 1998 The thyrotropin (TSH) hormone receptor: interaction with TSH and autoantibodies. Endocr Rev 19:673–716
Vassart G, Pardo L, Costagliola S 2004 A molecular dissection of the glycoprotein hormone receptors. Trends Biochem Sci 29:119–126
Latronico AC, Segaloff DL 1999 Naturally occurring mutations of the luteinizing-hormone receptor: lessons learned about reproductive physiology and G protein-coupled receptors. Am J Hum Genet 65:949–958
Themmen APN, Huhtaniemi IT 2000 Mutations of gonadotropins and gonadotropin receptors: elucidating the physiology and pathophysiology of pituitary-gonadal function. Endocr Rev 21:551–583
Dierich A, Sairam MR, Monaco L, Fimia GM, Gansmuller A, LeMeur M, Sassone-Corsi PS 1998 Impairing follicle-stimulating hormone (FSH) signaling in vivo: targeted disruption of the FSH receptor leads to aberrant gametogenesis and hormonal imbalance. Proc Natl Acad Sci USA 95:13612–13617
Zhang F-P, Poutanen M, Wilbertz J, Huhtaniemi I 2001 Normal prenatal but arrested postnatal sexual development of luteinizing hormone receptor knockout (LuRKO) mice. Mol Endocrinol 15:172–183
Lei ZM, Mishra S, Zou W, Xu B, Foltz M, Li X, Rao CV 2001 Targeted disruption of luteinizing hormone/human chorionic gonadotropin receptor gene. Mol Endocrinol 15:184–200
Fan QR, Hendricson WA 2005 Structure of the human follicle-stimulating hormone in complex with its receptors. Nature 433:269–277
Rao CV 2001 An overview of the past, present, and future of non-gonadal LH/hCG actions in reproductive biology and medicine. Semin Reprod Med 19:7–17
Rao CV 1996 The beginning of a new era in reproductive biology and medicine: expression of low levels of functional luteinizing hormone hormone/human chorionic gonadotropin receptors in nongonadal tissues. J Physiol Pharmacol 47:41–53
Rao CV, Lei ZM 2002 Consequences of targeted inactivation of LH receptors. Mol Cell Endocrinol 187:57–67
Rao CV 2001 Multiple novel roles of luteinizing hormone. Fertil Steril 76:1097–1100
Apaja PM, Aatsinki JT, Rajaniemi HJ, Pet?j?-Repo UE 2005 Expression of the mature luteinizing hormone receptor in rodent urogenital and adrenal tissues is developmentally regulated at a posttranslational level. Endocrinology 146:3224–3232
Tao Y-X, Johnson NB, Segaloff DL 2004 Constitutive and agonist-dependent self-association of the cell surface human lutropin receptor. J Biol Chem 279:5904–5914
Vuhai-Luuthi MT, Jolivet A, Jallal B, Salesse R, Bidart J-M, Houllier A, Guiochon-Mantel A, Garnier J, Milgrom E 1990 Monoclonal antibodies against luteinizing hormone receptor. Immunochemical characterization of the receptor. Endocrinology 127:2090–2098
VuHai-LuuThi MT, Misrahi M, Houillier A, Jolivet A, Milgrom E 1992 Variant forms of the pig lutropin/choriogonadotropin receptor. Biochemistry 31:8377–8383
Hipkin RW, Sánchez-Yagüe J, Ascoli M 1992 Identification and characterization of a luteinizing hormone/chorionic gonadotropin (LH/CG) receptor precursor in a human kidney cell line stably transfected with the rat luteal LH/CG receptor complementary DNA. Mol Endocrinol 6:2210–2218
Apaja PM, Harju KT, Aatsinki JT, Petaja-Repo UE, Rajaniemi HJ 2004 Identification and Structural Characterization of the Neuronal Luteinizing Hormone Receptor Associated with Sensory Systems. J Biol Chem 279:1899–1906
Keinanen KP, Kellokumpu S, Rajaniemi HJ 1987 Visualization of the rat ovarian lutropin receptor by ligand blotting. Mol Cell Endocrinol 49:33–38
Keinanen KP, Kellokumpu S, Metsikko MK, Rajaniemi HJ 1987 Purification and partial characterization of rat ovarian lutropin receptor. J Biol Chem 262:7920–7926
Min L, Ascoli M 2000 Effect of activating and inactivating mutations on the phosphorylation and trafficking of the human lutropin/choriogonadotropin receptor. Mol Endocrinol 14:1797–1810
Fabritz J, Ryan S, Ascoli M 1998 Transfected cells express mostly the intracellular precursor of the lutropin/choriogonadotropin receptor but this precursor binds choriogonadotropin with high affinity. Biochemistry 37:664–672
Davis DP, Rozell TG, Liu X, Segaloff DL 1997 The six N-linked carbohydrates of the lutropin/choriogonadotropin receptor are not absolutely required for correct folding, cell surface expression, hormone binding or signal transduction. Mol Endocrinol 11:550–562
Bradbury FA, Kawate N, Foster CM, Menon KMJ 1997 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 272:5921–5926
Zhu H, Wang H, Ascoli M 1995 The lutropin/choriogonadotropin (LH/CG) receptor is palmitoylated at intracellular cysteine residues. Mol Endocrinol 9:141–150
Min K-S, Liu X, Fabritz J, Jaquette J, Abell AN, Ascoli M 1998 Mutations that induce constitutive activation and mutations that impair signal transduction modulate the basal and/or agonist-stimulated internalization of the lutropin/choriogonadotropin receptor. J Biol Chem 273:34911–34919
Li S, Liu X, Ascoli M 2000 p38JAB1 Binds to the intracellular precursor of the lutropin/choriogonadotropin receptor and promotes its degradation. J Biol Chem 275:13386–13393
Rozell TG, Davis DP, Chai Y, Segaloff DL 1998 Association of gonadotropin receptor precursors with the protein folding chaperone calnexin. Endocrinology 139:1588–1593
Abell A, Liu X, Segaloff DL 1996 Deletions of portions of the extracellular loops of the lutropin/choriogonadotropin receptor decrease the binding affinity for ovine luteinizing hormone, but not for human choriogonadotropin, by preventing the formation of mature cell surface receptor. J Biol Chem 271:4518–4527
Menon KMJ, Munshi UM, Clouser CL, Nair AK 2004 Regulation of luteinizing hormone/human chorionic gonadotropin receptor expression: a perspective. Biol Reprod 70:861–866
Kumar TR, Wang Y, Matzuk MM 1996 Gonadotropins are essential modifier factors for gonadal tumor development in inhibin-deficient mice. Endocrinology 137:4210–4216
Kananen K, Rillianawati Paukku T, Markkula M, Rainio E-M, Huhtaniemi IT 1997 Suppression of gonadotropins inhibits gonadal tumorigenesis in mice transgenic for the mouse inhibin-a subunit promoter/SV40 T-antigen fusion gene. Endocrinology 138:3521–3531
Rilianawati, Paukku T, Kero J, Zhang F-P, Rahman N, Kananen K, Huhtaniemi I 1998 Direct luteinizing hormone action triggers adrenocortical tumorigenesis in castrated mice transgenic for the murine inhibin -subunit promoter/simian virus 40 T-antigen fusion gene. Mol Cell Endocrinol 12:801–809
Kero J, Poutanen M, Zhang FP, Rahman N, McNicol AM, Nilson JH, Keri RA, Huhtaniemi IT 2000 Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J. Clin. Invest 105:633–641
Lacroix A, Hamet P, Boutin JM 1999 Leuprolide acetate therapy in luteinizing hormone-dependent Cushing’s syndrome. New Engl J Med 341:1577–1581
Lacroix A, N'Diaye N, Tremblay J, Hamet P 2001 Ectopic and abnormal hormone receptors in adrenal Cushing’s syndrome. Endocr Rev 22:75–110(Mario Ascoli)