The '''luteinizing hormone/choriogonadotropin receptor''' ('''LHCGR'''), also '''lutropin/choriogonadotropin receptor''' ('''LCGR''') or '''luteinizing hormone receptor''' ('''LHR''') is a [[transmembrane receptor]] found predominantly in the [[ovary]] and [[testis]], but also many extragonadal organs such as the [[uterus]] and [[breast]]s. The receptor interacts with both [[luteinizing hormone]] (LH) and chorionic gonadotropins (such as [[Human chorionic gonadotropin|hCG]] in humans) and represents a [[G protein-coupled receptor]] (GPCR). Its activation is necessary for the hormonal functioning during reproduction.
== LHCGR gene ==
The [[Human genetics|gene]] for the LHCGR is found on [[chromosome 2]] p21 in humans, close to the [[FSH receptor]] gene. It consists of 70 kbp (versus 54 kpb for the FSHR).<ref name="FSHR">{{cite journal | vauthors = Simoni M, Gromoll J, Nieschlag E | title = The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology | journal = Endocrine Reviews | volume = 18 | issue = 6 | pages = 739–73 | date = Dec 1997 | pmid = 9408742 | doi = 10.1210/er.18.6.739 }}</ref> The gene is similar to the gene for the FSH receptor and the TSH receptor.
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== Receptor structure ==
{{PBB_Controls
The LHCGR consists of 674 amino acids and has a molecular mass of about 85–95 kDA based on the extent of glycosylation.<ref name="LHCGR">{{cite journal | vauthors = Ascoli M, Fanelli F, Segaloff DL | title = The lutropin/choriogonadotropin receptor, a 2002 perspective | journal = Endocrine Reviews | volume = 23 | issue = 2 | pages = 141–74 | date = Apr 2002 | pmid = 11943741 | doi = 10.1210/er.23.2.141 }}</ref>
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Like other GPCRs, the LHCG receptor possess seven membrane-spanning domains or [[transmembrane helix|transmembrane helices]].<ref name="pmid9558473">{{cite journal | vauthors = Dufau ML | title = The luteinizing hormone receptor | journal = Annual Review of Physiology | volume = 60 | issue = | pages = 461–96 | year = 1998 | pmid = 9558473 | doi = 10.1146/annurev.physiol.60.1.461 }}</ref> The extracellular domain of the receptor is heavily [[Glycosylation|glycosylated]]. These transmembrane domain contains two highly conserved [[cysteine]] residues, which build [[disulfide bond]]s to stabilize the receptor structure. The transmembrane part is highly homologous with other members of the rhodopsin family of GPCRs.<ref name="pmid24001578">{{cite journal | vauthors = Jiang X, Dias JA, He X | title = Structural biology of glycoprotein hormones and their receptors: insights to signaling | journal = Molecular and Cellular Endocrinology | volume = 382 | issue = 1 | pages = 424–51 | date = Jan 2014 | pmid = 24001578 | doi = 10.1016/j.mce.2013.08.021 }}</ref> The C-terminal domain is intracellular and brief, rich in [[serine]] and [[threonine]] residues for possible [[phosphorylation]].
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Luteinizing hormone/choriogonadotropin receptor
| Component = {{GNF_GO|id=GO:0005768 |text = endosome}} {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0005887 |text = integral to plasma membrane}}
| Process = {{GNF_GO|id=GO:0007165 |text = signal transduction}} {{GNF_GO|id=GO:0007187 |text = G-protein signaling, coupled to cyclic nucleotide second messenger}} {{GNF_GO|id=GO:0008584 |text = male gonad development}} {{GNF_GO|id=GO:0030539 |text = male genitalia development}}
| Orthologs = {{GNF_Ortholog_box
| Hs_EntrezGene = 3973
| Hs_Ensembl = ENSG00000138039
| Hs_RefseqProtein = NP_000224
| Hs_RefseqmRNA = NM_000233
| Hs_GenLoc_db =
| Hs_GenLoc_chr = 2
| Hs_GenLoc_start = 48768340
| Hs_GenLoc_end = 48836314
| Hs_Uniprot = P22888
| Mm_EntrezGene = 16867
| Mm_Ensembl = ENSMUSG00000024107
| Mm_RefseqmRNA = NM_013582
| Mm_RefseqProtein = NP_038610
| Mm_GenLoc_db =
| Mm_GenLoc_chr = 17
| Mm_GenLoc_start = 88649875
| Mm_GenLoc_end = 88700302
| Mm_Uniprot = P30730
}}
}}
The '''luteinizing hormone/choriogonadotropin receptor''' ('''LHCGR'''), also '''lutropin/choriogonadotropin receptor''' ('''LCGR''') is a [[transmembrane receptor]] found in ovary, testis and extragonodal organs like uterus, that receptor interacts with both [[luteinizing hormone]] (LH) and chorionic gonadotropins (such as [[Human chorionic gonadotropin|hCG]] in humans) and represents a [[G protein-coupled receptor]] (GPCR). It has also been called '''luteinizing hormone receptor''' ('''LHR'''). Its activation is necessary for the hormonal functioning during reproduction. LHCGRs are found in the [[ovary]], [[testis]], and many extragonadal tissues.
==LHCGR gene==
== Ligand binding and signal transduction ==
The gene for the LHCGR is found on [[chromosome 2]] p21 in humans, close to the [[FSH receptor]] gene. It consists of 70kbp (versus 54 kpb for the FSHR).<ref name="FSHR">{{cite journal | author = Simoni M, Gromoll J, Nieschlag E | title = The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology | journal = Endocr. Rev. | volume = 18 | issue = 6 | pages = 739–73 | year = 1997 | pmid = 9408742 | doi = 10.1210/er.18.6.739 | issn = }}</ref> The gene is similar to the gene for the FSH receptor and the TSH receptor.
Upon binding of LH to the external part of the membrane spanning receptor, a [[signal transduction|transduction of the signal]] takes place that activates the [[G protein]] that is bound to the receptor internally. With LH attached, the receptor shifts [[Chemical conformation|conformation]] and thus mechanically activates the G protein, which detaches from the receptor and activates the [[Cyclic adenosine monophosphate|cAMP]] system.<ref name="pmid9833610">{{cite journal |vauthors=Ryu KS, Gilchrist RL, Koo YB, Ji I, Ji TH |title=Gene, interaction, signal generation, signal divergence and signal transduction of the LH/CG receptor |journal=International Journal of Gynaecology and Obstetrics |volume=60 Suppl 1 |pages=S9-20 |date=Apr 1998 |pmid=9833610 |doi=10.1016/S0020-7292(98)80001-5}}</ref>
==Receptor structure==
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of LH (or CG) to the receptor shifts the equilibrium between active and inactive receptors. LH and LH-agonists shift the equilibrium in favor of active states; LH antagonists shift the equilibrium in favor of inactive states. For a cell to respond to LH only a small percentage (≈1%) of receptor sites need to be activated.
The LHCGR consists of 674 amino acids and has a molecular mass of about 85-95 kDA based on the extent of glycolization.<ref name="LHCGR">{{cite journal | author = Ascoli M, Fanelli F, Segaloff DL | title = The lutropin/choriogonadotropin receptor, a 2002 perspective | journal = Endocr. Rev. | volume = 23 | issue = 2 | pages = 141–74 | year = 2002 | pmid = 11943741 | doi = 10.1210/er.23.2.141 | issn = }}</ref>
[[Image:7TM_receptor.png|thumb|300px|The seven transmembrane α-helix structure of a G protein-coupled receptor such as LHCGR]]
=== Phosphorylation by cAMP-dependent protein kinases ===
Cyclic AMP-dependent protein kinases ([[protein kinase A]]) are activated by the signal chain coming from the G protein (that was activated by the LHCG-receptor) via [[adenylate cyclase]] and [[cyclic AMP]] (cAMP). These protein kinases are present as [[tetrameric protein|tetramers]] with two regulatory units and two catalytic units. Upon binding of cAMP to the regulatory units, the catalytic units are released and initiate the phosphorylation of proteins leading to the physiologic action. The cyclic AMP-regulatory [[protein dimer|dimers]] are degraded by [[phosphodiesterase]] and release 5’AMP. [[DNA]] in the [[cell nucleus]] binds to phosphorylated proteins through the [[cyclic AMP response element]] (CRE), which results in the activation of [[gene]]s.<ref name="FSHR" />
Like other GPCRs the LHCG receptor possess seven membrane-spanning domains or [[transmembrane helix|transmembrane helices]].<ref name="pmid9558473">{{cite journal | author = Dufau ML | title = The luteinizing hormone receptor | journal = Annu. Rev. Physiol. | volume = 60 | issue = | pages = 461–96 | year = 1998 | pmid = 9558473 | doi = 10.1146/annurev.physiol.60.1.461 | issn = }}</ref> The extracellular domain of the receptor is heavily [[Glycosylation|glycosylated]]. These transmembrane domain contains two highly conserved [[cysteine]] residues which build [[disulfide bond]]s to stabilize the receptor structure. The transmembrane part is highly homologous with other members of the rhodopsin family of GPCRs. The C-terminal domain is intracellular and brief, rich in [[serine]] and [[threonine]] residues for possible [[phosphorylation]].
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by [[prostaglandin]]s. Other cellular regulators that participate are the intracellular calcium concentration modified by [[phospholipase]], [[nitric acid]], and other growth factors.
==Ligand binding and signal transduction==
In a ''feedback mechanism'', these activated kinases phosphorylate the receptor. The longer the receptor remains active the more kinases are activated and the more receptors are phosphorylated.
Upon binding LH externally to the membrane, a [[signal transduction|transduction of the signal]] takes place that activates the [[G protein]] that is bound to the receptor internally. With LH attached, the receptor shifts [[Chemical conformation|conformation]] and thus mechanically activates the G protein, which detaches from the receptor and activates the [[cAMP]] system.<ref name="pmid9833610">{{cite journal | author = Ryu KS, Gilchrist RL, Koo YB, Ji I, Ji TH | title = Gene, interaction, signal generation, signal divergence and signal transduction of the LH/CG receptor | journal = International journal of gynaecology and obstetrics: the official organ of the International Federation of Gynaecology and Obstetrics | volume = 60 Suppl 1 | issue = | pages = S9–20 | year = 1998 | pmid = 9833610 | doi = 10.1016/S0020-7292(98)80001-5 | issn = }}</ref>
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of LH (or CG) to the receptor shifts the equilibrium between active and inactive receptors. LH and LH-agonists shift the equilibrium in favor of active states; LH antagonists shift the equilibrium in favor of inactive states. For a cell to respond to LH only a small percentage (~1%) of receptor sites need to be activated.
Other pathways of signaling exist for the LHCGR.<ref name="LHCGR" />
===Phosphorylation by cAMP-dependent protein kinases===
== Action ==
Cyclic AMP-dependent protein kinases ([[protein kinase A]]) are activated by the signal chain coming from the G protein (that was activated by the LHCG-receptor) via [[adenylate cyclase]] and [[cyclic AMP]] (cAMP). These protein kinases are present as [[tetramer]] with two regulatory units and two catalytic units. Upon binding of cAMP to the regulatory units, the catalytic units are released and initiate the phosphorylation of proteins leading to the physiologic action. The cyclic AMP-regulatory [[dimer]]s are degraded by [[phosphodiesterase]] and release 5’AMP. [[DNA]] in the [[cell nucleus]] binds to phosphorylated proteins through the [[cyclic AMP response element]] (CRE) which results in the activation of [[gene]]s.<ref name="FSHR"/>
[[File:Steroidogenesis.svg|thumb|Luteinizing hormone up-regulates cholesterol side chain cleaving enzyme in sensitive tissues, the first step of all human steroidogenesis. |389x389px]]It specifically acts to up-regulate the enzyme [[Cholesterol side-chain cleavage enzyme|cholesterol side chain cleaving enzyme]], which leads to the greater conversion of cholesterol into androgen precursors required to make many steroid hormones, including testosterone and estrogens.<ref>{{cite journal | vauthors = Dufau ML, Cigorraga S, Baukal AJ, Sorrell S, Bator JM, Neubauer JF, Catt KJ | title = Androgen biosynthesis in Leydig cells after testicular desensitization by luteinizing hormone-releasing hormone and human chorionic gonadotropin | journal = Endocrinology | volume = 105 | issue = 6 | pages = 1314–21 | date = Dec 1979 | pmid = 227658 | doi = 10.1210/endo-105-6-1314 | url = http://press.endocrine.org/doi/abs/10.1210/endo-105-6-1314 }}</ref>
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by [[prostaglandin]]s. Other cellular regulators are participate are the intracellular calcium concentration modified by [[phospholipase]], [[nitric acid]], and other growth factors.
=== Ovary ===
In the ovary, the LHCG receptor is necessary for follicular maturation and ovulation, as well as luteal function. Its expression requires appropriate hormonal stimulation by [[Follicle-stimulating hormone|FSH]] and [[estradiol]]. The LHCGR is present on [[granulosa cells]], [[theca]] cells, [[luteal]] cells, and interstitial cells<ref name="LHCGR"/> The LCGR is restimulated by increasing levels of [[chorionic gonadotropin]]s in case a [[pregnancy]] is developing. In turn, luteal function is prolonged and the endocrine milieu is supportive of the nascent pregnancy.
=== Testis ===
In the male the LHCGR has been identified on the [[Leydig cell]]s that are critical for [[testosterone]] production, and support [[spermatogenesis]].
In a ''feedback mechanism'', these activated kinases phosphorylate the receptor. The longer the receptor remains active, the more kinases are activated, the more receptors are phosphorylated.
Normal LHCGR functioning is critical for male fetal development, as the fetal Leydig cells produce [[testosterone]] to induce masculinization.
Other pathways of signaling exist for the LHCGR.<ref name="LHCGR"/>
=== Extragonadal ===
==Action==
LHCGR have been found in many types of extragonadal tissues, and the physiologic role of some has remained largely unexplored. Thus receptors have been found in the [[uterus]], [[sperm]], [[seminal vesicles]], [[prostate]], [[skin]], [[breast]], [[adrenal]]s, [[thyroid]], neural [[retina]], [[neuroendocrine]] cells, and (rat) [[brain]].<ref name="LHCGR"/><!--section: III. Expression of the LHR-->
===Ovary===
In the ovary, the LHCG receptor is necessary for follicular maturation and ovulation, as well as luteal function. Its expression requires appropriate hormonal stimulation by [[FSH]] and [[estradiol]]. The LHCGR is present on [[granulosa cells]], [[theca]] cells, [[luteal]] cells, and interstitial cells<ref name="LHCGR"/> The LCGR is restimulated by increasing levels of [[chorionic gonadotropin]]s in case a [[pregnancy]] is developing. In turn, luteal function is prolonged and the endocrine milieu is supportive of the nascent pregnancy.
===Testis===
== Receptor regulation ==
In the male the LHCGR has been identified on the [[Leydig cell]]s that are critical for [[testosterone]] production, and support [[spermatogenesis]].
[[Image:7TM receptor.png|thumb|326x326px|The seven transmembrane α-helix structure of a G protein-coupled receptor such as LHCGR]]
Normal LHCGR functioning is critical for male fetal development, as the fetal Leydig cells produce [[testosterone]] to induce masculinization.
=== Upregulation ===
[[Upregulation]] refers to the increase in the number of receptor sites on the membrane. Estrogen and FSH upregulate LHCGR sites in preparation for [[ovulation]]. After ovulation, the luteinized ovary maintains LHCGR s that allow activation in case there is an implantation.
===Extragonadal===
LHCGR have been found in many types of extragonadal tissues, and the physiologic role of some has remained largely unexplored. Thus receptors have been found in the [[uterus]], [[sperm]], [[seminal vesicles]], [[prostate]], [[skin]], [[breast]], [[adrenal]]s, [[thyroid]], neural [[retina]], [[neuroendocrine]] cells, and (rat) [[brain]].<ref name="LHCGR"/>
==Receptor regulation==
=== Desensitization ===
===Upregulation===
[[Upregulation]] refers to the increase in the number of receptor sites on the membrane. Estrogen and FSH upregulate LHCGR sites in preparation for [[ovulation]]. After ovulation, the luteinized ovary maintains LHCGR s that allow activation in case there is an implantation.
===Desensitization===
The LHCGRs become desensitized when exposed to LH for some time. A key reaction of this downregulation is the [[phosphorylation]] of the intracellular (or [[cytoplasm]]ic) receptor domain by [[protein kinase]]s. This process uncouples Gs protein from the LHCGR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
The LHCGRs become desensitized when exposed to LH for some time. A key reaction of this downregulation is the [[phosphorylation]] of the intracellular (or [[cytoplasm]]ic) receptor domain by [[protein kinase]]s. This process uncouples Gs protein from the LHCGR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
===Downregulation===
[[Downregulation]] refers to the decrease in the number of receptor sites. This can be accomplished by metabolizing bound LHCGR sites. The bound LCGR complex is brought by lateral migration to a “coated pit” where such units are concentrated and then stabilized by a framework of [[clathrin]]s. A pinched-off coated pit is internalized and degraded by [[lysosomes]]. Proteins may be metabolized or the receptor can be recycled. Use of long-acting agonists will downregulate the receptor population.
=== Downregulation ===
===Modulators===
[[Downregulation]] refers to the decrease in the number of receptor sites. This can be accomplished by metabolizing bound LHCGR sites. The bound LCGR complex is brought by lateral migration to a ''coated pit'', where such units are concentrated and then stabilized by a framework of [[clathrin]]s. A pinched-off coated pit is internalized and degraded by [[lysosomes]]. Proteins may be metabolized or the receptor can be recycled. Use of long-acting agonists will downregulate the receptor population.
=== Modulators ===
Antibodies to LHCGR can interfere with LHCGR activity.
Antibodies to LHCGR can interfere with LHCGR activity.
==LHCGR abnormalities==
== LHCGR abnormalities ==
Loss-of-function mutations in females can lead to [[infertility]]. In 46, XY individuals severe inactivation can cause male [[pseudohermaphroditism]], as fetal Leydig cells during may not respond and induce masculinization.<ref name="pmid10714363">{{cite journal | author = Wu SM, Chan WY | title = Male pseudohermaphroditism due to inactivating luteinizing hormone receptor mutations | journal = Arch. Med. Res. | volume = 30 | issue = 6 | pages = 495–500 | year = 1999 | pmid = 10714363 | doi = 10.1016/S0188-4409(99)00074-0 | issn = }}</ref> Less severe inactivation can result in [[hypospadias]] or a [[micropenis]].<ref name="LHCGR"/>
Loss-of-function mutations in females can lead to [[infertility]]. In 46, XY individuals severe inactivation can cause male [[pseudohermaphroditism]], as fetal Leydig cells during may not respond and induce masculinization.<ref name="pmid10714363">{{cite journal | vauthors = Wu SM, Chan WY | title = Male pseudohermaphroditism due to inactivating luteinizing hormone receptor mutations | journal = Archives of Medical Research | volume = 30 | issue = 6 | pages = 495–500 | year = 1999 | pmid = 10714363 | doi = 10.1016/S0188-4409(99)00074-0 }}</ref> Less severe inactivation can result in [[hypospadias]] or a [[micropenis]].<ref name="LHCGR"/>
==History==
== History ==
[[Alfred G. Gilman]] and [[Martin Rodbell]] received the 1994 [[Nobel Prize in Medicine and Physiology]] for the discovery of the G Protein System.
[[Alfred G. Gilman]] and [[Martin Rodbell]] received the 1994 [[Nobel Prize in Medicine and Physiology]] for the discovery of the G Protein System.
==References==
==I interactions ==
Luteinizing hormone/choriogonadotropin receptor has been shown to [[Protein-protein interaction|interact]] with [[GIPC1]].<ref name=pmid14507927>{{cite journal | vauthors = Hirakawa T, Galet C, Kishi M, Ascoli M | title = GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR | journal = The Journal of Biological Chemistry | volume = 278 | issue = 49 | pages = 49348–57 | date = Dec 2003 | pmid = 14507927 | doi = 10.1074/jbc.M306557200 }}</ref>
== References ==
{{Reflist|2}}
{{Reflist|2}}
==Further reading==
== Further reading ==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal | vauthors = Ji TH, Ryu KS, Gilchrist R, Ji I | title = Interaction, signal generation, signal divergence, and signal transduction of LH/CG and the receptor | journal = Recent Progress in Hormone Research | volume = 52 | issue = | pages = 431–53; discussion 454 | year = 1997 | pmid = 9238862 | doi = }}
| citations =
* {{cite journal | vauthors = Dufau ML | title = The luteinizing hormone receptor | journal = Annual Review of Physiology | volume = 60 | issue = | pages = 461–96 | year = 1998 | pmid = 9558473 | doi = 10.1146/annurev.physiol.60.1.461 }}
*{{cite journal | author=Ji TH, Ryu KS, Gilchrist R, Ji I |title=Interaction, signal generation, signal divergence, and signal transduction of LH/CG and the receptor. |journal=Recent Prog. Horm. Res. |volume=52 |issue= |pages= 431-53; discussion 454 |year= 1997 |pmid= 9238862 |doi= }}
* {{cite journal | vauthors = Ascoli M, Fanelli F, Segaloff DL | title = The lutropin/choriogonadotropin receptor, a 2002 perspective | journal = Endocrine Reviews | volume = 23 | issue = 2 | pages = 141–74 | date = Apr 2002 | pmid = 11943741 | doi = 10.1210/er.23.2.141 }}
* {{cite journal | vauthors = Fanelli F, Puett D | title = Structural aspects of luteinizing hormone receptor: information from molecular modeling and mutagenesis | journal = Endocrine | volume = 18 | issue = 3 | pages = 285–93 | date = Aug 2002 | pmid = 12450321 | doi = 10.1385/ENDO:18:3:285 }}
*{{cite journal | author=Amsterdam A, Hanoch T, Dantes A, ''et al.'' |title=Mechanisms of gonadotropin desensitization. |journal=Mol. Cell. Endocrinol. |volume=187 |issue= 1-2 |pages= 69-74 |year= 2003 |pmid= 11988313 |doi= }}
* {{cite journal | vauthors = Latronico AC, Segaloff DL | title = Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor | journal = Molecular and Cellular Endocrinology | volume = 260-262 | issue = | pages = 287–93 | date = Jan 2007 | pmid = 17055147 | pmc = 1785107 | doi = 10.1016/j.mce.2005.11.053 }}
*{{cite journal | author=Fanelli F, Puett D |title=Structural aspects of luteinizing hormone receptor: information from molecular modeling and mutagenesis. |journal=Endocrine |volume=18 |issue= 3 |pages= 285-93 |year= 2003 |pmid= 12450321 |doi= }}
* {{cite journal | vauthors = Nagayama Y, Russo D, Wadsworth HL, Chazenbalk GD, Rapoport B | title = Eleven amino acids (Lys-201 to Lys-211) and 9 amino acids (Gly-222 to Leu-230) in the human thyrotropin receptor are involved in ligand binding | journal = The Journal of Biological Chemistry | volume = 266 | issue = 23 | pages = 14926–30 | date = Aug 1991 | pmid = 1651314 | doi = }}
*{{cite journal | author=Latronico AC, Segaloff DL |title=Insights learned from L457(3.43)R, an activating mutant of the human lutropin receptor. |journal=Mol. Cell. Endocrinol. |volume=260-262 |issue= |pages= 287-93 |year= 2007 |pmid= 17055147 |doi= 10.1016/j.mce.2005.11.053 }}
* {{cite journal | vauthors = Jia XC, Oikawa M, Bo M, Tanaka T, Ny T, Boime I, Hsueh AJ | title = Expression of human luteinizing hormone (LH) receptor: interaction with LH and chorionic gonadotropin from human but not equine, rat, and ovine species | journal = Molecular Endocrinology | volume = 5 | issue = 6 | pages = 759–68 | date = Jun 1991 | pmid = 1922095 | doi = 10.1210/mend-5-6-759 }}
*{{cite journal | author=Nagayama Y, Russo D, Wadsworth HL, ''et al.'' |title=Eleven amino acids (Lys-201 to Lys-211) and 9 amino acids (Gly-222 to Leu-230) in the human thyrotropin receptor are involved in ligand binding. |journal=J. Biol. Chem. |volume=266 |issue= 23 |pages= 14926-30 |year= 1991 |pmid= 1651314 |doi= }}
* {{cite journal | vauthors = Minegishi T, Nakamura K, Takakura Y, Miyamoto K, Hasegawa Y, Ibuki Y, Igarashi M, Minegishi T | title = Cloning and sequencing of human LH/hCG receptor cDNA | journal = Biochemical and Biophysical Research Communications | volume = 172 | issue = 3 | pages = 1049–54 | date = Nov 1990 | pmid = 2244890 | doi = 10.1016/0006-291X(90)91552-4 | author8 = Minegish T [corrected to Minegishi T }}
*{{cite journal | author=Jia XC, Oikawa M, Bo M, ''et al.'' |title=Expression of human luteinizing hormone (LH) receptor: interaction with LH and chorionic gonadotropin from human but not equine, rat, and ovine species. |journal=Mol. Endocrinol. |volume=5 |issue= 6 |pages= 759-68 |year= 1991 |pmid= 1922095 |doi= }}
* {{cite journal | vauthors = Rousseau-Merck MF, Misrahi M, Atger M, Loosfelt H, Milgrom E, Berger R | title = Localization of the human luteinizing hormone/choriogonadotropin receptor gene (LHCGR) to chromosome 2p21 | journal = Cytogenetics and Cell Genetics | volume = 54 | issue = 1-2 | pages = 77–9 | year = 1991 | pmid = 2249480 | doi = 10.1159/000132962 }}
*{{cite journal | author=Minegishi T, Nakamura K, Takakura Y, ''et al.'' |title=Cloning and sequencing of human LH/hCG receptor cDNA. |journal=Biochem. Biophys. Res. Commun. |volume=172 |issue= 3 |pages= 1049-54 |year= 1990 |pmid= 2244890 |doi= }}
* {{cite journal | vauthors = Xie YB, Wang H, Segaloff DL | title = Extracellular domain of lutropin/choriogonadotropin receptor expressed in transfected cells binds choriogonadotropin with high affinity | journal = The Journal of Biological Chemistry | volume = 265 | issue = 35 | pages = 21411–4 | date = Dec 1990 | pmid = 2254302 | doi = }}
*{{cite journal | author=Rousseau-Merck MF, Misrahi M, Atger M, ''et al.'' |title=Localization of the human luteinizing hormone/choriogonadotropin receptor gene (LHCGR) to chromosome 2p21. |journal=Cytogenet. Cell Genet. |volume=54 |issue= 1-2 |pages= 77-9 |year= 1991 |pmid= 2249480 |doi= }}
* {{cite journal | vauthors = Frazier AL, Robbins LS, Stork PJ, Sprengel R, Segaloff DL, Cone RD | title = Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing | journal = Molecular Endocrinology | volume = 4 | issue = 8 | pages = 1264–76 | date = Aug 1990 | pmid = 2293030 | doi = 10.1210/mend-4-8-1264 }}
*{{cite journal | author=Xie YB, Wang H, Segaloff DL |title=Extracellular domain of lutropin/choriogonadotropin receptor expressed in transfected cells binds choriogonadotropin with high affinity. |journal=J. Biol. Chem. |volume=265 |issue= 35 |pages= 21411-4 |year= 1991 |pmid= 2254302 |doi= }}
* {{cite journal | vauthors = Keutmann HT, Charlesworth MC, Mason KA, Ostrea T, Johnson L, Ryan RJ | title = A receptor-binding region in human choriogonadotropin/lutropin beta subunit | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 84 | issue = 7 | pages = 2038–42 | date = Apr 1987 | pmid = 3470775 | pmc = 304579 | doi = 10.1073/pnas.84.7.2038 }}
*{{cite journal | author=Frazier AL, Robbins LS, Stork PJ, ''et al.'' |title=Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing. |journal=Mol. Endocrinol. |volume=4 |issue= 8 |pages= 1264-76 |year= 1991 |pmid= 2293030 |doi= }}
* {{cite journal | vauthors = Jiang X, Dreano M, Buckler DR, Cheng S, Ythier A, Wu H, Hendrickson WA, el Tayar N | title = Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions | journal = Structure | volume = 3 | issue = 12 | pages = 1341–53 | date = Dec 1995 | pmid = 8747461 | doi = 10.1016/S0969-2126(01)00272-6 }}
*{{cite journal | author=Keutmann HT, Charlesworth MC, Mason KA, ''et al.'' |title=A receptor-binding region in human choriogonadotropin/lutropin beta subunit. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=84 |issue= 7 |pages= 2038-42 |year= 1987 |pmid= 3470775 |doi= }}
* {{cite journal | vauthors = Atger M, Misrahi M, Sar S, Le Flem L, Dessen P, Milgrom E | title = Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5' non-coding regions | journal = Molecular and Cellular Endocrinology | volume = 111 | issue = 2 | pages = 113–23 | date = Jun 1995 | pmid = 7556872 | doi = 10.1016/0303-7207(95)03557-N }}
*{{cite journal | author=Atger M, Misrahi M, Sar S, ''et al.'' |title=Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5' non-coding regions. |journal=Mol. Cell. Endocrinol. |volume=111 |issue= 2 |pages= 113-23 |year= 1995 |pmid= 7556872 |doi= }}
* {{cite journal | vauthors = Latronico AC, Anasti J, Arnhold IJ, Mendonça BB, Domenice S, Albano MC, Zachman K, Wajchenberg BL, Tsigos C | title = A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 80 | issue = 8 | pages = 2490–4 | date = Aug 1995 | pmid = 7629248 | doi = 10.1210/jc.80.8.2490 }}
* {{cite journal | vauthors = Shenker A, Laue L, Kosugi S, Merendino JJ, Minegishi T, Cutler GB | title = A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty | journal = Nature | volume = 365 | issue = 6447 | pages = 652–4 | date = Oct 1993 | pmid = 7692306 | doi = 10.1038/365652a0 }}
*{{cite journal | author=Shenker A, Laue L, Kosugi S, ''et al.'' |title=A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty. |journal=Nature |volume=365 |issue= 6447 |pages= 652-4 |year= 1993 |pmid= 7692306 |doi= 10.1038/365652a0 }}
* {{cite journal | vauthors = Yano K, Saji M, Hidaka A, Moriya N, Okuno A, Kohn LD, Cutler GB | title = A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 80 | issue = 4 | pages = 1162–8 | date = Apr 1995 | pmid = 7714085 | doi = 10.1210/jc.80.4.1162 }}
*{{cite journal | author=Yano K, Saji M, Hidaka A, ''et al.'' |title=A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty. |journal=J. Clin. Endocrinol. Metab. |volume=80 |issue= 4 |pages= 1162-8 |year= 1995 |pmid= 7714085 |doi= }}
* {{cite journal | vauthors = Kremer H, Kraaij R, Toledo SP, Post M, Fridman JB, Hayashida CY, van Reen M, Milgrom E, Ropers HH, Mariman E | title = Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene | journal = Nature Genetics | volume = 9 | issue = 2 | pages = 160–4 | date = Feb 1995 | pmid = 7719343 | doi = 10.1038/ng0295-160 }}
*{{cite journal | author=Kremer H, Kraaij R, Toledo SP, ''et al.'' |title=Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene. |journal=Nat. Genet. |volume=9 |issue= 2 |pages= 160-4 |year= 1995 |pmid= 7719343 |doi= 10.1038/ng0295-160 }}
* {{cite journal | vauthors = Kosugi S, Van Dop C, Geffner ME, Rabl W, Carel JC, Chaussain JL, Mori T, Merendino JJ, Shenker A | title = Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty | journal = Human Molecular Genetics | volume = 4 | issue = 2 | pages = 183–8 | date = Feb 1995 | pmid = 7757065 | doi = 10.1093/hmg/4.2.183 }}
*{{cite journal | author=Kosugi S, Van Dop C, Geffner ME, ''et al.'' |title=Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty. |journal=Hum. Mol. Genet. |volume=4 |issue= 2 |pages= 183-8 |year= 1995 |pmid= 7757065 |doi= }}
* {{cite journal | vauthors = Kremer H, Mariman E, Otten BJ, Moll GW, Stoelinga GB, Wit JM, Jansen M, Drop SL, Faas B, Ropers HH | title = Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty | journal = Human Molecular Genetics | volume = 2 | issue = 11 | pages = 1779–83 | date = Nov 1993 | pmid = 8281137 | doi = 10.1093/hmg/2.11.1779 }}
*{{cite journal | author=Kremer H, Mariman E, Otten BJ, ''et al.'' |title=Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty. |journal=Hum. Mol. Genet. |volume=2 |issue= 11 |pages= 1779-83 |year= 1994 |pmid= 8281137 |doi= }}
The luteinizing hormone/choriogonadotropin receptor (LHCGR), also lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor (LHR) is a transmembrane receptor found predominantly in the ovary and testis, but also many extragonadal organs such as the uterus and breasts. The receptor interacts with both luteinizing hormone (LH) and chorionic gonadotropins (such as hCG in humans) and represents a G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning during reproduction.
The gene for the LHCGR is found on chromosome 2 p21 in humans, close to the FSH receptor gene. It consists of 70 kbp (versus 54 kpb for the FSHR).[1] The gene is similar to the gene for the FSH receptor and the TSH receptor.
Receptor structure
The LHCGR consists of 674 amino acids and has a molecular mass of about 85–95 kDA based on the extent of glycosylation.[2]
Like other GPCRs, the LHCG receptor possess seven membrane-spanning domains or transmembrane helices.[3] The extracellular domain of the receptor is heavily glycosylated. These transmembrane domain contains two highly conserved cysteine residues, which build disulfide bonds to stabilize the receptor structure. The transmembrane part is highly homologous with other members of the rhodopsin family of GPCRs.[4] The C-terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation.
Ligand binding and signal transduction
Upon binding of LH to the external part of the membrane spanning receptor, a transduction of the signal takes place that activates the G protein that is bound to the receptor internally. With LH attached, the receptor shifts conformation and thus mechanically activates the G protein, which detaches from the receptor and activates the cAMP system.[5]
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of LH (or CG) to the receptor shifts the equilibrium between active and inactive receptors. LH and LH-agonists shift the equilibrium in favor of active states; LH antagonists shift the equilibrium in favor of inactive states. For a cell to respond to LH only a small percentage (≈1%) of receptor sites need to be activated.
Phosphorylation by cAMP-dependent protein kinases
Cyclic AMP-dependent protein kinases (protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the LHCG-receptor) via adenylate cyclase and cyclic AMP (cAMP). These protein kinases are present as tetramers with two regulatory units and two catalytic units. Upon binding of cAMP to the regulatory units, the catalytic units are released and initiate the phosphorylation of proteins leading to the physiologic action. The cyclic AMP-regulatory dimers are degraded by phosphodiesterase and release 5’AMP. DNA in the cell nucleus binds to phosphorylated proteins through the cyclic AMP response element (CRE), which results in the activation of genes.[1]
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by prostaglandins. Other cellular regulators that participate are the intracellular calcium concentration modified by phospholipase, nitric acid, and other growth factors.
In a feedback mechanism, these activated kinases phosphorylate the receptor. The longer the receptor remains active the more kinases are activated and the more receptors are phosphorylated.
Other pathways of signaling exist for the LHCGR.[2]
Action
Error creating thumbnail: File missingLuteinizing hormone up-regulates cholesterol side chain cleaving enzyme in sensitive tissues, the first step of all human steroidogenesis.
It specifically acts to up-regulate the enzyme cholesterol side chain cleaving enzyme, which leads to the greater conversion of cholesterol into androgen precursors required to make many steroid hormones, including testosterone and estrogens.[6]
Ovary
In the ovary, the LHCG receptor is necessary for follicular maturation and ovulation, as well as luteal function. Its expression requires appropriate hormonal stimulation by FSH and estradiol. The LHCGR is present on granulosa cells, theca cells, luteal cells, and interstitial cells[2] The LCGR is restimulated by increasing levels of chorionic gonadotropins in case a pregnancy is developing. In turn, luteal function is prolonged and the endocrine milieu is supportive of the nascent pregnancy.
The seven transmembrane α-helix structure of a G protein-coupled receptor such as LHCGR
Upregulation
Upregulation refers to the increase in the number of receptor sites on the membrane. Estrogen and FSH upregulate LHCGR sites in preparation for ovulation. After ovulation, the luteinized ovary maintains LHCGR s that allow activation in case there is an implantation.
Desensitization
The LHCGRs become desensitized when exposed to LH for some time. A key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases. This process uncouples Gs protein from the LHCGR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
Downregulation
Downregulation refers to the decrease in the number of receptor sites. This can be accomplished by metabolizing bound LHCGR sites. The bound LCGR complex is brought by lateral migration to a coated pit, where such units are concentrated and then stabilized by a framework of clathrins. A pinched-off coated pit is internalized and degraded by lysosomes. Proteins may be metabolized or the receptor can be recycled. Use of long-acting agonists will downregulate the receptor population.
Modulators
Antibodies to LHCGR can interfere with LHCGR activity.
LHCGR abnormalities
Loss-of-function mutations in females can lead to infertility. In 46, XY individuals severe inactivation can cause male pseudohermaphroditism, as fetal Leydig cells during may not respond and induce masculinization.[7] Less severe inactivation can result in hypospadias or a micropenis.[2]
↑Jiang X, Dias JA, He X (Jan 2014). "Structural biology of glycoprotein hormones and their receptors: insights to signaling". Molecular and Cellular Endocrinology. 382 (1): 424–51. doi:10.1016/j.mce.2013.08.021. PMID24001578.
↑Ryu KS, Gilchrist RL, Koo YB, Ji I, Ji TH (Apr 1998). "Gene, interaction, signal generation, signal divergence and signal transduction of the LH/CG receptor". International Journal of Gynaecology and Obstetrics. 60 Suppl 1: S9–20. doi:10.1016/S0020-7292(98)80001-5. PMID9833610.
↑Wu SM, Chan WY (1999). "Male pseudohermaphroditism due to inactivating luteinizing hormone receptor mutations". Archives of Medical Research. 30 (6): 495–500. doi:10.1016/S0188-4409(99)00074-0. PMID10714363.
↑Hirakawa T, Galet C, Kishi M, Ascoli M (Dec 2003). "GIPC binds to the human lutropin receptor (hLHR) through an unusual PDZ domain binding motif, and it regulates the sorting of the internalized human choriogonadotropin and the density of cell surface hLHR". The Journal of Biological Chemistry. 278 (49): 49348–57. doi:10.1074/jbc.M306557200. PMID14507927.
Further reading
Ji TH, Ryu KS, Gilchrist R, Ji I (1997). "Interaction, signal generation, signal divergence, and signal transduction of LH/CG and the receptor". Recent Progress in Hormone Research. 52: 431–53, discussion 454. PMID9238862.
Ascoli M, Fanelli F, Segaloff DL (Apr 2002). "The lutropin/choriogonadotropin receptor, a 2002 perspective". Endocrine Reviews. 23 (2): 141–74. doi:10.1210/er.23.2.141. PMID11943741.
Amsterdam A, Hanoch T, Dantes A, Tajima K, Strauss JF, Seger R (Feb 2002). "Mechanisms of gonadotropin desensitization". Molecular and Cellular Endocrinology. 187 (1–2): 69–74. doi:10.1016/S0303-7207(01)00701-8. PMID11988313.
Fanelli F, Puett D (Aug 2002). "Structural aspects of luteinizing hormone receptor: information from molecular modeling and mutagenesis". Endocrine. 18 (3): 285–93. doi:10.1385/ENDO:18:3:285. PMID12450321.
Nagayama Y, Russo D, Wadsworth HL, Chazenbalk GD, Rapoport B (Aug 1991). "Eleven amino acids (Lys-201 to Lys-211) and 9 amino acids (Gly-222 to Leu-230) in the human thyrotropin receptor are involved in ligand binding". The Journal of Biological Chemistry. 266 (23): 14926–30. PMID1651314.
Jia XC, Oikawa M, Bo M, Tanaka T, Ny T, Boime I, Hsueh AJ (Jun 1991). "Expression of human luteinizing hormone (LH) receptor: interaction with LH and chorionic gonadotropin from human but not equine, rat, and ovine species". Molecular Endocrinology. 5 (6): 759–68. doi:10.1210/mend-5-6-759. PMID1922095.
Minegishi T, Nakamura K, Takakura Y, Miyamoto K, Hasegawa Y, Ibuki Y, Igarashi M, Minegishi T (Nov 1990). "Cloning and sequencing of human LH/hCG receptor cDNA". Biochemical and Biophysical Research Communications. 172 (3): 1049–54. doi:10.1016/0006-291X(90)91552-4. PMID2244890.
Rousseau-Merck MF, Misrahi M, Atger M, Loosfelt H, Milgrom E, Berger R (1991). "Localization of the human luteinizing hormone/choriogonadotropin receptor gene (LHCGR) to chromosome 2p21". Cytogenetics and Cell Genetics. 54 (1–2): 77–9. doi:10.1159/000132962. PMID2249480.
Xie YB, Wang H, Segaloff DL (Dec 1990). "Extracellular domain of lutropin/choriogonadotropin receptor expressed in transfected cells binds choriogonadotropin with high affinity". The Journal of Biological Chemistry. 265 (35): 21411–4. PMID2254302.
Frazier AL, Robbins LS, Stork PJ, Sprengel R, Segaloff DL, Cone RD (Aug 1990). "Isolation of TSH and LH/CG receptor cDNAs from human thyroid: regulation by tissue specific splicing". Molecular Endocrinology. 4 (8): 1264–76. doi:10.1210/mend-4-8-1264. PMID2293030.
Jiang X, Dreano M, Buckler DR, Cheng S, Ythier A, Wu H, Hendrickson WA, el Tayar N (Dec 1995). "Structural predictions for the ligand-binding region of glycoprotein hormone receptors and the nature of hormone-receptor interactions". Structure. 3 (12): 1341–53. doi:10.1016/S0969-2126(01)00272-6. PMID8747461.
Atger M, Misrahi M, Sar S, Le Flem L, Dessen P, Milgrom E (Jun 1995). "Structure of the human luteinizing hormone-choriogonadotropin receptor gene: unusual promoter and 5' non-coding regions". Molecular and Cellular Endocrinology. 111 (2): 113–23. doi:10.1016/0303-7207(95)03557-N. PMID7556872.
Latronico AC, Anasti J, Arnhold IJ, Mendonça BB, Domenice S, Albano MC, Zachman K, Wajchenberg BL, Tsigos C (Aug 1995). "A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty". The Journal of Clinical Endocrinology and Metabolism. 80 (8): 2490–4. doi:10.1210/jc.80.8.2490. PMID7629248.
Shenker A, Laue L, Kosugi S, Merendino JJ, Minegishi T, Cutler GB (Oct 1993). "A constitutively activating mutation of the luteinizing hormone receptor in familial male precocious puberty". Nature. 365 (6447): 652–4. doi:10.1038/365652a0. PMID7692306.
Yano K, Saji M, Hidaka A, Moriya N, Okuno A, Kohn LD, Cutler GB (Apr 1995). "A new constitutively activating point mutation in the luteinizing hormone/choriogonadotropin receptor gene in cases of male-limited precocious puberty". The Journal of Clinical Endocrinology and Metabolism. 80 (4): 1162–8. doi:10.1210/jc.80.4.1162. PMID7714085.
Kremer H, Kraaij R, Toledo SP, Post M, Fridman JB, Hayashida CY, van Reen M, Milgrom E, Ropers HH, Mariman E (Feb 1995). "Male pseudohermaphroditism due to a homozygous missense mutation of the luteinizing hormone receptor gene". Nature Genetics. 9 (2): 160–4. doi:10.1038/ng0295-160. PMID7719343.
Kosugi S, Van Dop C, Geffner ME, Rabl W, Carel JC, Chaussain JL, Mori T, Merendino JJ, Shenker A (Feb 1995). "Characterization of heterogeneous mutations causing constitutive activation of the luteinizing hormone receptor in familial male precocious puberty". Human Molecular Genetics. 4 (2): 183–8. doi:10.1093/hmg/4.2.183. PMID7757065.
Kremer H, Mariman E, Otten BJ, Moll GW, Stoelinga GB, Wit JM, Jansen M, Drop SL, Faas B, Ropers HH (Nov 1993). "Cosegregation of missense mutations of the luteinizing hormone receptor gene with familial male-limited precocious puberty". Human Molecular Genetics. 2 (11): 1779–83. doi:10.1093/hmg/2.11.1779. PMID8281137.
