FSH-receptor
Encyclopedia
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 hormonal functioning of FSH. FSHRs are found in the ovary
, testis, and uterus
.
s.
The FSHR consists of 695 amino acids and has a molecular mass of about 76 kDa. Like other GPCRs, the FSH-receptor possesses seven membrane-spanning domains or transmembrane helices
.
that activates the G protein
that is bound to the receptor internally takes place. With FSH 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 FSH to the receptor shifts the equilibrium between active and inactive receptors. FSH and FSH-agonists shift the equilibrium in favor of active states; FSH antagonists shift the equilibrium in favor of inactive states. For a cell to respond to FSH, only a small percentage (~1%) of receptor sites need to be activated.
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 gene
s.
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by prostaglandin
s. Other cellular regulators are participate are the intracellular calcium concentration modified by phospholipase
, nitric acid
, and other growth factors.
The FSH receptor can also activate the extracellular signal-regulated kinases (ERK). 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.
s.
In the male, the FSH receptor has been identified on the Sertoli cell
s that are critical for spermatogenesis
.
The FSHR is expressed during the luteal phase in the secretory endometrium
of the uterus.
FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of carcinogenic tumors.
s to produce estrogen
s. This synergistic activity of estrogen and FSH allows for follicle growth and development in the ovary.
of the intracellular (or cytoplasm
ic) receptor domain by protein kinase
s. This process uncouples Gs protein from the FSHR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
s. 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.
may have mutation
s in the gene for FSHR, making them more sensitive to gonadotropin stimulation.
Women with 46 XX gonadal dysgenesis
experience primary amenorrhea with hypergonadotropic hypogonadism
. There are forms of 46 xx gonadal dysgenesis wherein abnormalities in the FSH-receptor have been reported and are thought to be the cause of the hypogonadism.
Polymorphism
may affect FSH receptor populations and lead to poorer responses in infertile women receiving FSH medication for IVF.
and Martin Rodbell
received the 1994 Nobel Prize in Medicine and Physiology for the discovery of the G Protein System.
Follicle-stimulating hormone
Follicle-stimulating hormone is a hormone found in humans and other animals. It is synthesized and secreted by gonadotrophs of the anterior pituitary gland. FSH regulates the development, growth, pubertal maturation, and reproductive processes of the body. FSH and Luteinizing hormone act...
(FSH) and represents a G protein-coupled receptor
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
(GPCR). Its activation is necessary for the hormonal functioning of FSH. FSHRs are found in the ovary
Ovary
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in anatomically female individuals are analogous to testes in anatomically male individuals, in that they are both gonads and endocrine glands.-Human anatomy:Ovaries...
, testis, and uterus
Uterus
The uterus or womb is a major female hormone-responsive reproductive sex organ of most mammals including humans. One end, the cervix, opens into the vagina, while the other is connected to one or both fallopian tubes, depending on the species...
.
FSHR gene
The gene for the FSHR is found on chromosome 2 p21 in humans. The gene sequence of the FSHR consists of about 2,080 nucleotideNucleotide
Nucleotides are molecules that, when joined together, make up the structural units of RNA and DNA. In addition, nucleotides participate in cellular signaling , and are incorporated into important cofactors of enzymatic reactions...
s.
Receptor structure
Transmembrane helix
Transmembrane domain usually denotes a single transmembrane alpha helix of a transmembrane protein. It is called a "domain" because an alpha-helix in a membrane can fold independently from the rest of the protein, similar to domains of water-soluble proteins...
.
- The extracellular domain of the receptor is glycosylatedGlycosylationGlycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
.
- The transmembrane domain contains two highly conserved cysteineCysteineCysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
residues that build disulfide bondDisulfide bondIn chemistry, a disulfide bond is a covalent bond, usually derived by the coupling of two thiol groups. The linkage is also called an SS-bond or disulfide bridge. The overall connectivity is therefore R-S-S-R. The terminology is widely used in biochemistry...
s to stabilize the receptor structure. A highly conserved Asp-Arg-Tyr triplet motif is present and may be of importance to transmit the signal.
- The C-terminal domain is intracellular and brief, rich in serineSerineSerine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
and threonineThreonineThreonine is an α-amino acid with the chemical formula HO2CCHCHCH3. Its codons are ACU, ACA, ACC, and ACG. This essential amino acid is classified as polar...
residues for possible phosphorylationPhosphorylationPhosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
.
Ligand binding and signal transduction
Upon binding FSH externally to the membrane, a transduction of the signalSignal transduction
Signal transduction occurs when an extracellular signaling molecule activates a cell surface receptor. In turn, this receptor alters intracellular molecules creating a response...
that activates the G protein
G protein
G proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
that is bound to the receptor internally takes place. With FSH attached, the receptor shifts conformation and, thus, mechanically activates the G protein, which detaches from the receptor and activates the cAMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
system.
It is believed that a receptor molecule exists in a conformational equilibrium between active and inactive states. The binding of FSH to the receptor shifts the equilibrium between active and inactive receptors. FSH and FSH-agonists shift the equilibrium in favor of active states; FSH antagonists shift the equilibrium in favor of inactive states. For a cell to respond to FSH, 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 FSH-receptor) via adenylate cyclaseAdenylate cyclase
Adenylate cyclase is part of the G protein signalling cascade, which transmits chemical signals from outside the cell across the membrane to the inside of the cell ....
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
Phosphodiesterase
A phosphodiesterase is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below...
and release 5’AMP. DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
in the cell nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
binds to phosphorylated proteins through the cyclic AMP response element (CRE), which results in the activation of gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
s.
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by prostaglandin
Prostaglandin
A prostaglandin is any member of a group of lipid compounds that are derived enzymatically from fatty acids and have important functions in the animal body. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring....
s. Other cellular regulators are participate are the intracellular calcium concentration modified by phospholipase
Phospholipase
A phospholipase is an enzyme that hydrolyzes phospholipids into fatty acids and other lipophilic substances. There are four major classes, termed A, B, C and D, distinguished by the type of reaction which they catalyze:*Phospholipase A...
, nitric acid
Nitric acid
Nitric acid , also known as aqua fortis and spirit of nitre, is a highly corrosive and toxic strong acid.Colorless when pure, older samples tend to acquire a yellow cast due to the accumulation of oxides of nitrogen. If the solution contains more than 86% nitric acid, it is referred to as fuming...
, and other growth factors.
The FSH receptor can also activate the extracellular signal-regulated kinases (ERK). 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.
Action
In the ovary, the FSH receptor is necessary for follicular development and expressed on the granulosa cellGranulosa cell
A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete in the ovary of mammals.-Anatomy and function:...
s.
In the male, the FSH receptor has been identified on the Sertoli cell
Sertoli cell
A Sertoli cell is a 'nurse' cell of the testes that is part of a seminiferous tubule.It is activated by follicle-stimulating hormone and has FSH-receptor on its membranes.-Functions:...
s that are critical for spermatogenesis
Spermatogenesis
Spermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
.
The FSHR is expressed during the luteal phase in the secretory endometrium
Endometrium
-Function:The endometrium is the innermost glandular layer and functions as a lining for the uterus, preventing adhesions between the opposed walls of the myometrium, thereby maintaining the patency of the uterine cavity. During the menstrual cycle or estrous cycle, the endometrium grows to a...
of the uterus.
FSH receptor is selectively expressed on the surface of the blood vessels of a wide range of carcinogenic tumors.
Upregulation
Upregulation refers to the increase in the number of receptor site on the membrane. Estrogen upregulates FSH receptor sites. In turn, FSH stimulates granulosa cellGranulosa cell
A granulosa cell or follicular cell is a somatic cell of the sex cord that is closely associated with the developing female gamete in the ovary of mammals.-Anatomy and function:...
s to produce estrogen
Estrogen
Estrogens , oestrogens , or œstrogens, are a group of compounds named for their importance in the estrous cycle of humans and other animals. They are the primary female sex hormones. Natural estrogens are steroid hormones, while some synthetic ones are non-steroidal...
s. This synergistic activity of estrogen and FSH allows for follicle growth and development in the ovary.
Desensitization
The FSHR become desensitized when exposed to FSH for some time. A key reaction of this downregulation is the phosphorylationPhosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
of the intracellular (or cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic) receptor domain by protein kinase
Protein kinase
A protein kinase is a kinase enzyme that modifies other proteins by chemically adding phosphate groups to them . Phosphorylation usually results in a functional change of the target protein by changing enzyme activity, cellular location, or association with other proteins...
s. This process uncouples Gs protein from the FSHR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system.
Downregulation
Downregulation refers to the decrease in the number of receptor sites. This can be accomplished by metabolizing bound FSHR sites. The bound FSH-receptor complex is brought by lateral migration to a "coated pit," where such units are concentrated and then stabilized by a framework of clathrinClathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
s. 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.
FSHR abnormalities
Some patients with ovarian hyperstimulation syndromeOvarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome is a complication from some forms of fertility medication. Most cases are mild, but a small proportion are severe.-Causative medications:...
may have mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the gene for FSHR, making them more sensitive to gonadotropin stimulation.
Women with 46 XX gonadal dysgenesis
XX gonadal dysgenesis
This syndrome is inherited as an autosomal disease. It affects both males and females but the phenotype differs. In both sexes sensorineural deafness occurs but in females ovarian dysgenesis also occurs....
experience primary amenorrhea with hypergonadotropic hypogonadism
Hypogonadism
Hypogonadism is a medical term for decreased functional activity of the gonads. Low testosterone is caused by a decline or deficiency in gonadal production of testosterone in males...
. There are forms of 46 xx gonadal dysgenesis wherein abnormalities in the FSH-receptor have been reported and are thought to be the cause of the hypogonadism.
Polymorphism
Polymorphism (biology)
Polymorphism in biology occurs when two or more clearly different phenotypes exist in the same population of a species — in other words, the occurrence of more than one form or morph...
may affect FSH receptor populations and lead to poorer responses in infertile women receiving FSH medication for IVF.
History
Alfred G. GilmanAlfred G. Gilman
Alfred Goodman Gilman is an American pharmacologist and biochemist. He shared the 1994 Nobel Prize in Physiology or Medicine with Martin Rodbell for their discoveries regarding G-proteins....
and Martin Rodbell
Martin Rodbell
Martin Rodbell 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...
received the 1994 Nobel Prize in Medicine and Physiology for the discovery of the G Protein System.