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37-433: 1XWD , 4AY9 , 4MQW 2492 14309 ENSG00000170820 ENSMUSG00000032937 P23945 P35378 NM_000145 NM_181446 NM_013523 NP_000136 NP_852111 NP_038551 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

74-430: A database is that it saves time and power to obtain new effective compounds. Another approach of structure-based drug design is about combinatorially mapping ligands, which is referred to as receptor-based drug design. In this case, ligand molecules are engineered within the constraints of a binding pocket by assembling small pieces in a stepwise manner. These pieces can be either atoms or molecules. The key advantage of such

111-409: A method is that novel structures can be discovered. Granulosa cell 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 . In the primordial ovarian follicle , and later in follicle development ( folliculogenesis ), granulosa cells advance to form

148-461: A multilayered cumulus oophorus surrounding the oocyte in the preovulatory or antral (or Graafian) follicle. The major functions of granulosa cells include the production of sex steroids , as well as myriad growth factors thought to interact with the oocyte during its development. The sex steroid production begins with follicle-stimulating hormone (FSH) from the anterior pituitary, stimulating granulosa cells to convert androgens (coming from

185-420: A subviral component to the cytoplasmic side of the cellular membrane. In the case of poliovirus , it is known in vitro that interactions with receptors cause conformational rearrangements which release a virion protein called VP4.The N terminus of VP4 is myristylated and thus hydrophobic【 myristic acid =CH 3 (CH 2 ) 12 COOH】. It is proposed that the conformational changes induced by receptor binding result in

222-489: A ten-fold higher rate than MGCs in response to FSH. During expansion CCs also produce a mucified matrix required for ovulation. Cell culture of granulosa cells can be performed in vitro . Plating density (number of cells per volume of culture medium) plays a critical role for the differentiation. A lower plating density makes granulosa cells exhibit estrogen production, while a higher plating density makes them appear as progesterone producing theca lutein cells . In

259-505: A transporter for amino acids, and Aldoa, Eno1, Ldh1, Pfkp, Pkm2, and Tpi1, enzymes responsible for glycolysis. MGCs are more steroidogenically active and have higher levels of mRNA expression of steroidogenic enzymes such as cytochrome P450. MGCs produce an increasing amount of estrogen which leads to the LH surge . Following the LH surge, cumulus cells undergo cumulus expansion, in which they proliferate at

296-401: Is about determining ligands for a given receptor. This is usually accomplished through database queries, biophysical simulations, and the construction of chemical libraries. In each case, a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. This approach is usually referred to as ligand-based drug design. The key advantage of searching

333-435: Is displaced by guanosine triphosphate (GTP), thus activating the α subunit, which then dissociates from the β and γ subunits. The activated α subunit can further affect intracellular signaling proteins or target functional proteins directly. If the membrane receptors are denatured or deficient, the signal transduction can be hindered and cause diseases. Some diseases are caused by disorders of membrane receptor function. This

370-499: Is due to deficiency or degradation of the receptor via changes in the genes that encode and regulate the receptor protein. The membrane receptor TM4SF5 influences the migration of hepatic cells and hepatoma . Also, the cortical NMDA receptor influences membrane fluidity, and is altered in Alzheimer's disease. When the cell is infected by a non-enveloped virus, the virus first binds to specific membrane receptors and then passes itself or

407-555: Is necessary for the hormonal functioning of FSH. FSHRs are found in the ovary , testis , and uterus . The gene for the FSHR is found on chromosome 2 p21 in humans. The gene sequence of the FSHR consists of about 2,080 nucleotides . 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 . Upon initial binding to

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444-440: Is the native protein conformation. As two molecules of acetylcholine both bind to the binding sites on α subunits, the conformation of the receptor is altered and the gate is opened, allowing for the entry of many ions and small molecules. However, this open and occupied state only lasts for a minor duration and then the gate is closed, becoming the closed and occupied state. The two molecules of acetylcholine will soon dissociate from

481-420: The 7TM superfamily , the transmembrane domain includes a ligand binding pocket. The intracellular (or cytoplasmic ) domain of the receptor interacts with the interior of the cell or organelle, relaying the signal. There are two fundamental paths for this interaction: Signal transduction processes through membrane receptors involve the external reactions, in which the ligand binds to a membrane receptor, and

518-471: The cell nucleus binds to phosphorylated proteins through the cyclic AMP response element (CRE), which results in the activation of genes . 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. The FSH receptor can also activate

555-723: The epidermal growth factor (EGF) receptor binds with its ligand EGF, the two receptors dimerize and then undergo phosphorylation of the tyrosine residues in the enzyme portion of each receptor molecule. This will activate the tyrosine kinase and catalyze further intracellular reactions. G protein-coupled receptors comprise a large protein family of transmembrane receptors. They are found only in eukaryotes . The ligands which bind and activate these receptors include: photosensitive compounds, odors , pheromones , hormones , and neurotransmitters . These vary in size from small molecules to peptides and large proteins . G protein-coupled receptors are involved in many diseases, and thus are

592-505: The extracellular signal-regulated kinases (ERK). In a feedback mechanism , these activated kinases phosphorylate the receptor. In the ovary, the FSH receptor is necessary for follicular development and expressed on the granulosa cells . In the male, the FSH receptor has been identified on the Sertoli cells that are critical for spermatogenesis . The FSHR is expressed during the luteal phase in

629-444: The nicotinic acetylcholine receptor , the transmembrane domain forms a protein pore through the membrane, or around the ion channel . Upon activation of an extracellular domain by binding of the appropriate ligand, the pore becomes accessible to ions, which then diffuse. In other receptors, the transmembrane domains undergo a conformational change upon binding, which affects intracellular conditions. In some receptors, such as members of

666-522: The oogonia become invaginated in the gonadal ridge . The embryological origin of granulosa cells remains controversial. In the 1970s, evidence emerged that the first cells to make contact with the oogonia were of mesonephric origin. It was suggested that mesonephric cells already closely associated with the oogonia proliferated throughout development to form the granulosa cell layer. Recently, this hypothesis has been challenged with some thorough histology . Sawyer et al. hypothesized that in sheep most of

703-422: The thecal cells ) to estradiol by aromatase during the follicular phase of the menstrual cycle . However, after ovulation the granulosa cells turn into granulosa lutein cells that produce progesterone . The progesterone may maintain a potential pregnancy and causes production of a thick cervical mucus that inhibits sperm entry into the uterus. In the development of the urinary and reproductive organs ,

740-869: The FSHR gene may be implicated in subfertility in males Follicle-stimulating hormone (FSH) is an agonist of the FSHR. Small-molecule positive allosteric modulators of the FSHR have been developed. Alfred G. Gilman and Martin Rodbell received the 1994 Nobel Prize in Medicine and Physiology for "their discovery of G-proteins and the role of these proteins in signal transduction in cells". Transmembrane receptor Many membrane receptors are transmembrane proteins . There are various kinds, including glycoproteins and lipoproteins . Hundreds of different receptors are known and many more have yet to be studied. Transmembrane receptors are typically classified based on their tertiary (three-dimensional) structure. If

777-508: 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. Cyclic AMP-dependent protein kinases ( protein kinase A ) are activated by

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814-504: The LRR region of FSHR, FSH reshapes its conformation to form a new pocket. FSHR then inserts its sulfotyrosine from the hinge loop into the pockets and activates the 7-helical transmembrane domain. This event leads to a transduction of the signal that activates the Gs protein that is bound to the receptor internally. With FSH attached, the receptor shifts conformation and, thus, mechanically activates

851-509: The attachment of myristic acid on VP4 and the formation of a channel for RNA. Through methods such as X-ray crystallography and NMR spectroscopy , the information about 3D structures of target molecules has increased dramatically, and so has structural information about the ligands. This drives rapid development of structure-based drug design . Some of these new drugs target membrane receptors. Current approaches to structure-based drug design can be divided into two categories. The first category

888-540: The bilayer several times, the external domain comprises loops entwined through the membrane. By definition, a receptor's main function is to recognize and respond to a type of ligand. For example, a neurotransmitter , hormone , or atomic ions may each bind to the extracellular domain as a ligand coupled to receptor. Klotho is an enzyme which effects a receptor to recognize the ligand ( FGF23 ). Two most abundant classes of transmembrane receptors are GPCR and single-pass transmembrane proteins . In some receptors, such as

925-465: The development of the oocyte in a paracrine fashion. Mural granulosa cells (MGC) line the follicular wall and surround the fluid-filled antrum. The oocyte secretes factors that determine the functional differences between CCs and MGCs. CCs primarily support growth and development of the oocyte whereas MGCs primarily serve an endocrine function and support the growth of the follicle. Cumulus cells aid in oocyte development and show higher expression of SLC38A3,

962-509: 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 . Alternative splicing of

999-409: The granulosa cells develop from cells of the mesothelium (i.e., epithelial cells from the presumptive surface epithelium of the ovary). In 2013, it was proposed that both granulosa cells and the ovarian surface epithelial cells are instead derived from a precursor cell called gonadal-ridge epithelial-like cell. Cumulus cells (CC) surround the oocyte. They provide nutrients to the oocyte and influence

1036-408: The internal reactions, in which intracellular response is triggered. Signal transduction through membrane receptors requires four parts: Membrane receptors are mainly divided by structure and function into 3 classes: The ion channel linked receptor ; The enzyme-linked receptor ; and The G protein-coupled receptor . During the signal transduction event in a neuron, the neurotransmitter binds to

1073-524: 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 clathrins . A pinched-off coated pit is internalized and degraded by lysosomes . Proteins may be metabolized or the receptor can be recycled. Antibodies to FSHR can interfere with FSHR activity. Some patients with ovarian hyperstimulation syndrome may have mutations in

1110-410: The ovary. The FSHR become desensitized when exposed to FSH 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 FSHR. Another way to desensitize is to uncouple the regulatory and catalytic units of the cAMP system. Downregulation refers to the decrease in

1147-628: The receptor and alters the conformation of the protein. This opens the ion channel, allowing extracellular ions into the cell. Ion permeability of the plasma membrane is altered, and this transforms the extracellular chemical signal into an intracellular electric signal which alters the cell excitability . The acetylcholine receptor is a receptor linked to a cation channel. The protein consists of four subunits: alpha (α), beta (β), gamma (γ), and delta (δ) subunits. There are two α subunits, with one acetylcholine binding site each. This receptor can exist in three conformations. The closed and unoccupied state

Follicle-stimulating hormone receptor - Misplaced Pages Continue

1184-859: The receptor, returning it to the native closed and unoccupied state. As of 2009, there are 6 known types of enzyme-linked receptors : Receptor tyrosine kinases ; Tyrosine kinase associated receptors; Receptor-like tyrosine phosphatases ; Receptor serine / threonine kinases ; Receptor guanylyl cyclases and histidine kinase associated receptors. Receptor tyrosine kinases have the largest population and widest application. The majority of these molecules are receptors for growth factors such as epidermal growth factor (EGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), hepatocyte growth factor (HGF), nerve growth factor (NGF) and hormones such as insulin . Most of these receptors will dimerize after binding with their ligands, in order to activate further signal transductions. For example, after

1221-446: 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. Upregulation refers to the increase in the number of receptor sites on the membrane. Estrogen upregulates FSH receptor sites. In turn, FSH stimulates granulosa cells to produce estrogens . This synergistic activity of estrogen and FSH allows for follicle growth and development in

1258-594: The signal chain coming from the Gs protein (that was activated by the FSH-receptor) via adenylate cyclase 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

1295-418: The sort of membrane and cellular function. Receptors are often clustered on the membrane surface, rather than evenly distributed. Two models have been proposed to explain transmembrane receptors' mechanism of action. Transmembrane receptors in plasma membrane can usually be divided into three parts. The extracellular domain is just externally from the cell or organelle . If the polypeptide chain crosses

1332-506: The targets of many modern medicinal drugs. There are two principal signal transduction pathways involving the G-protein coupled receptors: the cAMP signaling pathway and the phosphatidylinositol signaling pathway. Both are mediated via G protein activation. The G-protein is a trimeric protein, with three subunits designated as α, β, and γ. In response to receptor activation, the α subunit releases bound guanosine diphosphate (GDP), which

1369-517: The three-dimensional structure is unknown, they can be classified based on membrane topology . In the simplest receptors, polypeptide chains cross the lipid bilayer once, while others, such as the G-protein coupled receptors , cross as many as seven times. Each cell membrane can have several kinds of membrane receptors, with varying surface distributions. A single receptor may also be differently distributed at different membrane positions, depending on

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