The luteinizing hormone/choriogonadotropin receptor (LHCGR), also lutropin/choriogonadotropin receptor (LCGR) or luteinizing hormone receptor (LHR) is a
transmembrane receptor
Cell surface receptors (membrane receptors, transmembrane receptors) are receptor (biochemistry), receptors that are embedded in the cell membrane, plasma membrane of cell (biology), cells. They act in cell signaling by receiving (binding to) ex ...
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
A testicle or testis (plural testes) is the male reproductive gland or gonad in all bilaterians, including humans. It is homologous to the female ovary. The functions of the testes are to produce both sperm and androgens, primarily testostero ...
, 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
Luteinizing hormone (LH, also known as luteinising hormone, lutropin and sometimes lutrophin) is a hormone produced by gonadotropic cells in the anterior pituitary gland. The production of LH is regulated by gonadotropin-releasing hormone (GnRH) ...
(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
Chromosome 2 is one of the twenty-three pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 2 is the second-largest human chromosome, spanning more than 242 million base pairs and representing almost e ...
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 horm ...
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
A transmembrane domain (TMD) is a membrane-spanning protein domain. TMDs generally adopt an alpha helix topological conformation, although some TMDs such as those in porins can adopt a different conformation. Because the interior of the lipid bi ...
.
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 bond
In biochemistry, a disulfide (or disulphide in British English) refers to a functional group with the structure . The linkage is also called an SS-bond or sometimes a disulfide bridge and is usually derived by the coupling of two thiol groups. In ...
s 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
Heterotrimeric G protein, also sometimes referred to as the ''"large" G proteins'' (as opposed to the subclass of smaller, monomeric small GTPases) are membrane-associated G proteins that form a Heteromer, heterotrimeric complex. The biggest no ...
. 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
Adenylate cyclase (EC 4.6.1.1, also commonly known as adenyl cyclase and adenylyl cyclase, abbreviated AC) is an enzyme with systematic name ATP diphosphate-lyase (cyclizing; 3′,5′-cyclic-AMP-forming). It catalyzes the following reaction:
:A ...
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
In cell biology, protein kinase A (PKA) is a family of enzymes whose activity is dependent on cellular levels of cyclic AMP (cAMP). PKA is also known as cAMP-dependent protein kinase (). PKA has several functions in the cell, including regulatio ...
) 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
CREB-TF (CREB, cAMP response element-binding protein) is a cellular transcription factor. It binds to certain DNA sequences called cAMP response elements (CRE), thereby increasing or decreasing the transcription of the genes. CREB was first des ...
, 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 so ...
s (CRE); this process results in the activation or inactivation of
gene transcription
Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins are said to produce messenger RNA (mRNA). Other segments of DNA are copied into RNA molecules calle ...
.
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
![Steroidogenesis](https://upload.wikimedia.org/wikipedia/commons/1/13/Steroidogenesis.svg)
The LHCG receptor's main function is the regulation of
steroidogenesis
A steroid is a biologically active organic compound with four rings arranged in a specific molecular configuration. Steroids have two principal biological functions: as important components of cell membranes that alter membrane fluidity; and a ...
. 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
Estradiol (E2), also spelled oestradiol, is an estrogen steroid hormone and the major female sex hormone. It is involved in the regulation of the estrous and menstrual female reproductive cycles. Estradiol is responsible for the development of f ...
. 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
In biology, a theca (plural thecae) is a sheath or a covering.
Botany
In botany, the theca is related to plant's flower anatomy. The theca of an angiosperm consists of a pair of microsporangia that are adjacent to each other and share a commo ...
cells,
luteal cells, and interstitial cells
The LCGR is restimulated by increasing levels of
chorionic gonadotropin
Human chorionic gonadotropin (hCG) is a hormone for the maternal recognition of pregnancy produced by trophoblast cells that are surrounding a growing embryo (syncytiotrophoblast initially), which eventually forms the placenta after implantation ...
s 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
The seminal vesicles (also called vesicular glands, or seminal glands) are a pair of two convoluted tubular glands that lie behind the urinary bladder of some male mammals. They secrete fluid that partly composes the semen.
The vesicles are 5†...
,
prostate
The prostate is both an Male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found only in some mammals. It differs between species anatomically, ...
,
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
Neuroendocrine cells are cells that receive neuronal input (through neurotransmitters released by nerve cells or neurosecretory cells) and, as a consequence of this input, release messenger molecules ( hormones) into the blood. In this way they b ...
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
Ovulation is the release of eggs from the ovaries. In women, this event occurs when the ovarian follicles rupture and release the secondary oocyte ovarian cells. After ovulation, during the luteal phase, the egg will be available to be fertilized ...
. 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 kinase
A protein kinase is a kinase which selectively modifies other proteins by covalently adding phosphates to them (phosphorylation) as opposed to kinases which modify lipids, carbohydrates, or other molecules. Phosphorylation usually results in a fu ...
s. 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
Arrestins (abbreviated Arr) are a small family of proteins important for regulating signal transduction at G protein-coupled receptors.
Arrestins were first discovered as a part of a conserved two-step mechanism for regulating the activity of ...
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
endosome
Endosomes are a collection of intracellular sorting organelles in eukaryotic cells. They are parts of endocytic membrane transport pathway originating from the trans Golgi network. Molecules or ligands internalized from the plasma membrane can ...
s, some of which are recycled to the cell surface while others are targeted to
lysosomes
A lysosome () is a membrane-bound organelle found in many animal cells. They are spherical vesicles that contain hydrolytic enzymes that can break down many kinds of biomolecules. A lysosome has a specific composition, of both its membrane prote ...
. 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 and
Martin Rodbell
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. He shared the 1994 Nobel Prize in Physiology or Medicine with Alfred G. Gilman fo ...
received the 1994
Nobel Prize in Medicine and Physiology 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
GIPC PDZ domain containing family, member 1 (GIPC1) is a protein that in humans is encoded by the ''GIPC1'' gene. GIPC was originally identified as it binds specifically to the C terminus of RGS-GAIP, a protein involved in the regulation of G prot ...
.
References
Further reading
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External links
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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