Luteinizing hormone/choriogonadotropin receptor

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 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

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).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 = ] 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 glycolization.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 = ]

Like other GPCRs the LHCG receptor possess seven membrane-spanning domains or transmembrane helices.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 = ] 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. The C-terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation.

Ligand binding and signal transduction

Upon binding LH externally to the membrane, 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.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 = ]

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 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 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.

The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by prostaglandins. Other cellular regulators are 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, the more receptors are phosphorylated.

Other pathways of signaling exist for the LHCGR.

Action

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 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.

Testis

In the male the LHCGR has been identified on the Leydig cells that are critical for testosterone production, and support spermatogenesis.

Normal LHCGR functioning is critical for male fetal development, as the fetal Leydig cells produce testosterone to induce masculinization.

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, adrenals, thyroid, neural retina, neuroendocrine cells, and (rat) brain.

Receptor regulation

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.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 = ] Less severe inactivation can result in hypospadias or a micropenis.

History

Alfred G. Gilman and Martin Rodbell received the 1994 Nobel Prize in Medicine and Physiology for the discovery of the G Protein System.

References

Further reading

PBB_Further_reading
citations =
*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 | 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
*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=
*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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | 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 | author=Latronico AC, Anasti J, Arnhold IJ, "et al." |title=A novel mutation of the luteinizing hormone receptor gene causing male gonadotropin-independent precocious puberty. |journal=J. Clin. Endocrinol. Metab. |volume=80 |issue= 8 |pages= 2490–4 |year= 1995 |pmid= 7629248 |doi=
*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 | 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 | 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 | 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 | 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=

External links

* [http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2987 IUPHAR GPCR Database - LH Receptor]
* [http://gris.ulb.ac.be GRIS: Glycoprotein-hormone Receptor Information System]
*MeshName|LH-hCG+Receptors

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