LH-receptor
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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 The ovary is an organ in the female reproductive system that produces an ovum. When released, this travels down the fallopian tube into the uterus, where it may become fertilized by a sperm. There is an ovary () found on each side of the body. ...
and testis, but also many extragonadal organs such as the
uterus The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
and
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...
s. The receptor interacts with both luteinizing hormone (LH) and chorionic gonadotropins (such as hCG in humans) and represents a
G protein-coupled receptor G protein-coupled receptors (GPCRs), also known as seven-(pass)-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptors, and G protein-linked receptors (GPLR), form a large group of evolutionarily-related p ...
(GPCR). Its activation is necessary for the hormonal functioning during reproduction.


LHCGR gene

The
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
for the LHCGR is found on chromosome 2 p21 in humans, close to the
FSH receptor 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). Its activation is necessary for the hormo ...
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 Glycosylation is the reaction in which a carbohydrate (or 'glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not alw ...
. These transmembrane domains contain two highly conserved
cysteine Cysteine (symbol Cys or C; ) is a semiessential proteinogenic amino acid with the formula . The thiol side chain in cysteine often participates in enzymatic reactions as a nucleophile. When present as a deprotonated catalytic residue, sometime ...
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 Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
and
threonine Threonine (symbol Thr or T) is an amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated −NH form under biological conditions), a carboxyl group (which is in the deprotonated −COOâ ...
residues for possible
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
.


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. This process results in the activation of a heterotrimeric G protein. Binding of LH to the receptor shifts its conformation. The activated receptor promotes the binding of GTP to the G protein and its subsequent activation. After binding GTP, the G protein heterotrimer detaches from the receptor and disassembles. The alpha-subunit Gs binds adenylate cyclase and activates the
cAMP Camp may refer to: Outdoor accommodation and recreation * Campsite or campground, a recreational outdoor sleeping and eating site * a temporary settlement for nomads * Camp, a term used in New England, Northern Ontario and New Brunswick to descri ...
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 towards the active form of the receptor. 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 cascade originated by the activation of the G protein Gs by the LHCG-receptor. Activated Gs binds the enzyme adenylate cyclase and this leads to the production of
cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...
(cAMP). Cyclin AMP-dependent protein kinases are present as
tetramer A tetramer () (''tetra-'', "four" + '' -mer'', "parts") is an oligomer formed from four monomers or subunits. The associated property is called ''tetramery''. An example from inorganic chemistry is titanium methoxide with the empirical formula Ti ...
s with two regulatory subunits and two catalytic subunits. Upon binding of cAMP to the regulatory subunits, the catalytic units are released and initiate the phosphorylation of proteins leading to the physiologic action. Cyclic AMP is degraded by
phosphodiesterase A phosphodiesterase (PDE) is an enzyme that breaks a phosphodiester bond. Usually, ''phosphodiesterase'' refers to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many oth ...
and release 5’AMP. One of the targets of protein kinase A is the Cyclic AMP Response Element Binding Protein, CREB, which binds DNA in the
cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...
via direct interactions with specific DNA sequences called
cyclic AMP response element Cycle, cycles, or cyclic may refer to: Anthropology and social sciences * Cyclic history, a theory of history * Cyclical theory, a theory of American political history associated with Arthur Schlesinger, Sr. * Social cycle, various cycles in soc ...
s (CRE); this process results in the activation or inactivation of gene transcription. The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by
prostaglandin The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derive ...
s. Other cellular regulators that participate are the intracellular calcium concentration regulated by
phospholipase C Phospholipase C (PLC) is a class of membrane-associated enzymes that cleave phospholipids just before the phosphate group (see figure). It is most commonly taken to be synonymous with the human forms of this enzyme, which play an important role ...
activation,
nitric oxide Nitric oxide (nitrogen oxide or nitrogen monoxide) is a colorless gas with the formula . It is one of the principal oxides of nitrogen. Nitric oxide is a free radical: it has an unpaired electron, which is sometimes denoted by a dot in its che ...
, and other growth factors. Other pathways of signaling exist for the LHCGR.


Action

The LHCG receptor's main function is the regulation of steroidogenesis. This is accomplished by increasing the intracellular levels of the enzyme cholesterol side chain cleaving enzyme, a member of the
cytochrome P450 Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
family. This leads to increased conversion of cholesterol into androgen precursors required to make many steroid hormones, including testosterone and estrogens.


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 A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete (called an oocyte or egg) in the ovary of mammals. Structure and function In the primordial ovarian follicle, and l ...
, theca cells,
luteal The corpus luteum (Latin for "yellow body"; plural corpora lutea) is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is th ...
cells, and interstitial cells The LCGR is restimulated by increasing levels of chorionic gonadotropins in case a
pregnancy Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins. Pregnancy usually occurs by sexual intercourse, but ca ...
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 Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral ...
s that are critical for
testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...
production, and support
spermatogenesis Spermatogenesis is the process by which haploid spermatozoa develop from germ cells in the seminiferous tubules of the testis. This process starts with the mitotic division of the stem cells located close to the basement membrane of the tubule ...
. 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.


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 The uterus (from Latin ''uterus'', plural ''uteri'') or womb () is the organ in the reproductive system of most female mammals, including humans that accommodates the embryonic and fetal development of one or more embryos until birth. The uter ...
,
sperm Sperm is the male reproductive cell, or gamete, in anisogamous forms of sexual reproduction (forms in which there is a larger, female reproductive cell and a smaller, male one). Animals produce motile sperm with a tail known as a flagellum, whi ...
, seminal vesicles, prostate,
skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate animal, with three main functions: protection, regulation, and sensation. Other cuticle, animal coverings, such as the arthropod exoskeleton, have diffe ...
,
breast The breast is one of two prominences located on the upper ventral region of a primate's torso. Both females and males develop breasts from the same embryological tissues. In females, it serves as the mammary gland, which produces and secret ...
,
adrenal The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which ...
s,
thyroid The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
, neural
retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then ...
, neuroendocrine cells, and (rat)
brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...
.


Receptor regulation


Upregulation

Upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...
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 In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
of the intracellular (or
cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...
ic) receptor domain by protein kinases. This process uncouples Gs protein from the LHCGR.


Downregulation

Downregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...
refers to the decrease in the number of receptor molecules. This is usually the result of receptor
endocytosis Endocytosis is a cellular process in which substances are brought into the cell. The material to be internalized is surrounded by an area of cell membrane, which then buds off inside the cell to form a vesicle containing the ingested material. E ...
. In this process, the bound LCGR-hormone complex binds arrestin and concentrates in clathrin coated pits. Clathrin coated pits recruit
dynamin Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the "dynamin superfamily", which includes classical dynamins, dynamin-like proteins, Mx proteins, OPA1, mitofusins, and GBPs. Members of the dynamin fa ...
and pinch off from the cell surface, becoming clathrin-coated vesicles. Clathrin-coated vesicles are processed into endosomes, some of which are recycled to the cell surface while others are targeted to lysosomes. Receptors targeted to lysosomes are degraded. Use of long-acting agonists will downregulate the receptor population by promoting their endocytosis.


Modulators

Antibodies to LHCGR can interfere with LHCGR activity.


LHCGR abnormalities

Loss-of-function mutations in females can lead to
infertility Infertility is the inability of a person, animal or plant to reproduce by natural means. It is usually not the natural state of a healthy adult, except notably among certain eusocial species (mostly haplodiploid insects). It is the normal state ...
. In 46, XY individuals severe inactivation can cause male
pseudohermaphroditism Pseudohermaphroditism is a condition in which an individual has a matching chromosomal and gonadal tissue (ovary or testis) sex, but mismatching external genitalia. Female pseudohermaphroditism refers to an individual with ovaries and external gen ...
, as fetal Leydig cells during may not respond and thus interfere with masculinization. Less severe inactivation can result in
hypospadias Hypospadias is a common variation in fetal development of the penis in which the urethra does not open from its usual location in the head of the penis. It is the second-most common birth abnormality of the male reproductive system, affecting abou ...
or a
micropenis Micropenis is an unusually small penis. A common criterion is a dorsal (measured on top) penile length of at least 2.5 standard deviations smaller than the mean human penis size (stretched penile length less than 9.3 cm (3.67 in) in adults). ...
.


History

Alfred G. Gilman Alfred Goodman Gilman (July 1, 1941 – December 23, 2015) was an American pharmacologist and biochemist. He and Martin Rodbell shared the 1994 Nobel Prize in Physiology or Medicine "for their discovery of G-proteins and the role of these prot ...
and Martin Rodbell received the 1994
Nobel Prize in Medicine and Physiology The Nobel Prize in Physiology or Medicine is awarded yearly by the Nobel Assembly at the Karolinska Institute for outstanding discoveries in physiology or medicine. The Nobel Prize is not a single prize, but five separate prizes that, according ...
for the discovery of the G Protein System.


Interactions

Luteinizing hormone/choriogonadotropin receptor has been shown to
interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...
with GIPC1.


References


Further reading

* * * * * * * * * * * * * * * * * * * * *


External links

*
SSFA-GPHR: Sequence Structure Function Analysis of Glycoprotein Hormone ReceptorsGRIS: Glycoprotein-hormone Receptor Information System
* {{DEFAULTSORT:Luteinizing hormone choriogonadotropin receptor G protein-coupled receptors Gonadotropin-releasing hormone and gonadotropins Signal transduction