The luteinizing hormone/choriogonadotropin receptor (LHCGR), also lutropin/choriogonadotropin receptor (LCGR) is a transmembrane receptor that 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. Hugo is a masculine name. ... The Entrez logo The Entrez Global Query Cross-Database Search System allows access to databases at the National Center for Biotechnology Information (NCBI) website. ... The Mendelian Inheritance in Man project is a database that catalogues all the known diseases with a genetic component, and - when possible - links them to the relevant genes in the human genome. ... The National Center for Biotechnology Information (NCBI) is part of the US National Library of Medicine (NLM), which is a branch of the US National Institutes of Health. ... Swiss-Prot is a curated biological database of protein sequences created in 1986 by Amos Bairoch during his PhD and developed by the Swiss Institute of Bioinformatics and the European Bioinformatics Institute. ... Short and long arms Chromosome. ... Chromosome 2 is one of the 23 pairs of chromosomes in humans. ... Transmembrane receptors are integral membrane proteins, which reside and operate typically within a cells plasma membrane, but also in the membranes of some subcellular compartments and organelles. ... Luteinizing hormone (LH) is a hormone synthesized and secreted by gonadotropes in the anterior lobe of the pituitary gland. ... HCG may stand for Human chorionic gonadotropin (usually abbreviated with a lowercase h: hCG) H computer graphics (pornographic drawings in H games) This is a disambiguation page — a navigational aid which lists other pages that might otherwise share the same title. ... Figure 1. ... Human female internal reproductive anatomy Ovaries are egg-producing reproductive organs found in female organisms. ... Human male anatomy The testicles, known medically as testes (singular testis), are the male generative glands in animals. ...

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).^[1] The gene is similar to the gene for the FSH receptor and the TSH receptor. Chromosome 2 is one of the 23 pairs of chromosomes in humans[1]. People normally have two copies of this chromosome. ... The follicle stimulating hormone receptor or FSH-receptor (FSHR) is a transmembrane receptor that interacts with the follicle stimulating hormone (FSH) and represents a G protein-coupled receptor (GPCR). ...

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.^[2]

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

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 cysteine residues which build disulfide bonds to stabilize the receptor structure. The transmembrane part is highly homologous with other CPCRs. The C-terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation. Image File history File links 7TM_receptor. ... Image File history File links 7TM_receptor. ... Within an integral membrane protein, a transmembrane helix is a segment that is alpha-helical in structure, roughly 20 amino acids in length and (though it may be presumed to lie within the protein, out of contact with the surrounding lipid bilayer) is said to span the membrane. ... Glycosylation is the process or result of addition of saccharides to proteins and lipids. ... Cysteine is a naturally occurring amino acid which has a thiol group and is found in most proteins, though only in small quantities. ... In chemistry, a disulfide bond is a single covalent bond derived from the coupling of thiol groups. ... Serine is one of the 20 natural amino acids. ... Threonine is one of the 20 natural amino acids. ... Phosphorylation is the addition of a phosphate (PO4) group to a protein or a small molecule. ...

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. In biology, signal transduction is any process by which a cell converts one kind of signal or stimulus into another. ... G-proteins, short for guanine nucleotide binding proteins, are a family of proteins involved in second messenger cascades. ... In chemistry, a chemical conformation is the spatial arrangement of atoms in a molecule. ... Camp may mean: Gatherings of people: Campsite Temporary settlement of a band of foragers. ...

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.^[1] In cell biology, cAMP-dependent protein kinase (cAPK), also known as protein kinase A (PKA)(EC 2. ... Adenylate cyclase Adenylate cyclase (EC 4. ... Structure of cAMP Cyclic adenosine monophosphate (cAMP, cyclic AMP or 3-5-cyclic adenosine monophosphate) is a molecule that is important in many biological processes; it is derived from adenosine triphosphate (ATP). ... A tetramer is a protein with four subunits (tetrameric). ... Sucrose, or common table sugar, is composed of glucose and fructose. ... A phosphodiesterase (PDE) is an enzyme that catalyzes the hydrolysis of phosphodiester bonds. ... The general structure of a section of DNA Deoxyribonucleic acid (DNA) is a nucleic acid that contains the genetic instructions for the biological development of a cellular form of life or a virus. ... The eukaryotic cell nucleus. ... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ...

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. Chemical structure of prostaglandin E1 (PGE1). ... A phospholipase is an enzyme that converts phospholipids into fatty acids and other lipophilic substances. ... The chemical compound nitric acid (HNO3), otherwise known as aqua fortis or spirit of nitre, is an aqueous solution of hydrogen nitrate (anhydrous nitric acid). ...

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.^[2]

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^[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. Follicle stimulating hormone (FSH) is a hormone produced by gonadotropes in the anterior pituitary gland. ... Estradiol (17-beta estradiol) (also oestradiol) is a sex hormone. ... A pregnant woman near the end of her term Pregnancy is the carrying of one or more embryos or fetuses by female mammals, including humans, inside their bodies. ...

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. Leydig cells, also known as interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testes. ... Testosterone is a steroid hormone from the androgen group. ... This article or section is in need of attention from an expert on the subject. ... Testosterone is a steroid hormone from the androgen group. ...

Extragonadal

LHCGR have been found in many types of extragonadal tissues, and the physiologic role 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.^[2]

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. Upregulation is the process by which a cell increases the number of receptors to a given hormone or neurotransmitter to improve its sensitivity to this molecule. ... Ovulation is the process in the menstrual cycle by which a mature ovarian follicle ruptures and discharges an ovum (also known as an oocyte, female gamete, or casually, an egg) that participates in reproduction. ...

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. Phosphorylation is the addition of a phosphate (PO4) group to a protein or a small molecule. ... Organelles. ... A protein kinase is an enzyme that modifies other proteins by chemically adding phosphate groups to them (phosphorylation). ...

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. Downregulation is the process by which a cell decreases the number of receptors to a given hormone or neurotransmitter to reduce its sensitivity to this molecule. ... Clathrin is a protein that is the major constituent of the coat of the coated pits and coated vesicles formed during endocytosis of materials at the surface of cells. ... Lysosomes are organelles in eukaryotic cells that contain digestive enzymes to digest macromolecules. ...

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. Less severe inactivation can result in hypospadias or a micropenis.^[2] Infertility is the inability to naturally conceive a child or to carry a pregnancy to full term. ... An intersexual or intersex person (or animal of any unisexual species) is one who is born with genitalia and/or secondary sexual characteristics of indeterminate sex, or which combine features of both sexes. ... Hypospadias is a birth defect of the urethra in the male that involves an abnormally placed urethral meatus (opening). ... Micropenis is a medical term that describes an unusually small penis in a human male. ...

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 Goodman Gilman (born July 1, 1941) is an American scientist. ... Martin Rodbell won a Nobel Prize in 1994 Martin Rodbell (December 1, 1925- December 7, 1998) was an American biochemist and molecular endocrinologist who is best known for his discovery of G-proteins. ... List of Nobel Prize laureates in Physiology or Medicine from 1901 to the present day. ...

References

External links

• IUPHAR GPCR Database - LH Receptor
• GRIS: Glycoprotein-hormone Receptor Information System