Luteinizing hormone/choriogonadotropin receptor

The luteinizing hormone/choriogonadotropin receptor (LHCGR), also lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor (LHR) is a is_associated_with::transmembrane receptor found predominantly in the is_associated_with::ovary and is_associated_with::testis, but also many extragonadal organs such as the is_associated_with::uterus and is_associated_with::breasts. The receptor interacts with both is_associated_with::luteinizing hormone (LH) and chorionic gonadotropins (such as hCG in humans) and represents a is_associated_with::G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning during reproduction.

LHCGR gene
The gene for the LHCGR is found on is_associated_with::chromosome 2 p21 in humans, close to the is_associated_with::FSH receptor gene. It consists of 70 kbp (versus 54 kpb for the FSHR). 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.



Like other GPCRs, the LHCG receptor possess seven membrane-spanning domains or transmembrane helices. The extracellular domain of the receptor is heavily  glycosylated. These transmembrane domain contains two highly conserved is_associated_with::cysteine residues, which build is_associated_with::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 is_associated_with::serine and is_associated_with::threonine residues for possible is_associated_with::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 is_associated_with::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.

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 (is_associated_with::protein kinase A) are activated by the signal chain coming from the G protein (that was activated by the LHCG-receptor) via is_associated_with::adenylate cyclase and is_associated_with::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 is_associated_with::phosphodiesterase and release 5’AMP. is_associated_with::DNA in the is_associated_with::cell nucleus binds to phosphorylated proteins through the is_associated_with::cyclic AMP response element (CRE), which results in the activation of is_associated_with::genes.

The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by is_associated_with::prostaglandins. Other cellular regulators that participate are the intracellular calcium concentration modified by is_associated_with::phospholipase, is_associated_with::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.

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 is_associated_with::estradiol. The LHCGR is present on is_associated_with::granulosa cells, is_associated_with::theca cells, is_associated_with::luteal cells, and interstitial cells The LCGR is restimulated by increasing levels of is_associated_with::chorionic gonadotropins in case a is_associated_with::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 is_associated_with::Leydig cells that are critical for is_associated_with::testosterone production, and support is_associated_with::spermatogenesis.

Normal LHCGR functioning is critical for male fetal development, as the fetal Leydig cells produce is_associated_with::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 is_associated_with::uterus, is_associated_with::sperm, is_associated_with::seminal vesicles, is_associated_with::prostate, is_associated_with::skin, is_associated_with::breast, is_associated_with::adrenals, is_associated_with::thyroid, neural is_associated_with::retina, is_associated_with::neuroendocrine cells, and (rat) is_associated_with::brain.

Upregulation
is_associated_with::Upregulation refers to the increase in the number of receptor sites on the membrane. Estrogen and FSH upregulate LHCGR sites in preparation for is_associated_with::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 is_associated_with::phosphorylation of the intracellular (or is_associated_with::cytoplasmic) receptor domain by is_associated_with::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
is_associated_with::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 is_associated_with::clathrins. A pinched-off coated pit is internalized and degraded by is_associated_with::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 is_associated_with::infertility. In 46, XY individuals severe inactivation can cause male is_associated_with::pseudohermaphroditism, as fetal Leydig cells during may not respond and induce masculinization. Less severe inactivation can result in is_associated_with::hypospadias or a is_associated_with::micropenis.

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

Interactions
Luteinizing hormone/choriogonadotropin receptor has been shown to interact with is_associated_with::GIPC1.