Luteinizing hormone/choriogonadotropin receptor

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Available structures
PDBOrtholog search: PDBe RCSB
AliasesLHCGR, HHG, LCGR, LGR2, LH/CG-R, LH/CGR, LHR, LHRHR, LSH-R, ULG5, Luteinizing hormone/choriogonadotropin receptor
External IDsOMIM: 152790 MGI: 96783 HomoloGene: 37276 GeneCards: LHCGR
Gene location (Human)
Chromosome 2 (human)
Chr.Chromosome 2 (human)[1]
Chromosome 2 (human)
Genomic location for LHCGR
Genomic location for LHCGR
Band2p16.3Start48,686,774 bp[1]
End48,755,730 bp[1]
RNA expression pattern
PBB GE LHCGR 207240 s at fs.png
More reference expression data
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 2: 48.69 – 48.76 MbChr 17: 88.72 – 88.79 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

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.

LHCGR gene[edit]

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).[5] The gene is similar to the gene for the FSH receptor and the TSH receptor.

Receptor structure[edit]

The LHCGR consists of 674 amino acids and has a molecular mass of about 85–95 kDA based on the extent of glycosylation.[6]

Like other GPCRs, the LHCG receptor possess seven membrane-spanning domains or transmembrane helices.[7] The extracellular domain of the receptor is heavily glycosylated. These transmembrane domains contain 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.[8] The C-terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation.

Ligand binding and signal transduction[edit]

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.[9]

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[edit]

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.[5]

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.[6]


Luteinizing 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.[10]


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[6] 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.


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 androstenedione which is converted to testosterone in fetal Sertoli cells to induce masculinization.


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.[6]

Receptor regulation[edit]

The seven transmembrane α-helix structure of a G protein-coupled receptor such as LHCGR


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.


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 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.


Antibodies to LHCGR can interfere with LHCGR activity.

LHCGR abnormalities[edit]

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 thus interfere with masculinization.[11] Less severe inactivation can result in hypospadias or a micropenis.[6]


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

I interactions[edit]

Luteinizing hormone/choriogonadotropin receptor has been shown to interact with GIPC1.[12]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000138039 - Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024107 - Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Simoni M, Gromoll J, Nieschlag E (Dec 1997). "The follicle-stimulating hormone receptor: biochemistry, molecular biology, physiology, and pathophysiology". Endocrine Reviews. 18 (6): 739–73. doi:10.1210/er.18.6.739. PMID 9408742.
  6. ^ a b c d e 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. PMID 11943741.
  7. ^ Dufau ML (1998). "The luteinizing hormone receptor". Annual Review of Physiology. 60: 461–96. doi:10.1146/annurev.physiol.60.1.461. PMID 9558473.
  8. ^ 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. PMID 24001578.
  9. ^ 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. PMID 9833610. S2CID 4798893.
  10. ^ Dufau ML, Cigorraga S, Baukal AJ, Sorrell S, Bator JM, Neubauer JF, Catt KJ (Dec 1979). "Androgen biosynthesis in Leydig cells after testicular desensitization by luteinizing hormone-releasing hormone and human chorionic gonadotropin". Endocrinology. 105 (6): 1314–21. doi:10.1210/endo-105-6-1314. PMID 227658.
  11. ^ 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. PMID 10714363.
  12. ^ 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. PMID 14507927.

Further reading[edit]

External links[edit]