Theluteinizing hormone/choriogonadotropin receptor (LHCGR), alsolutropin/choriogonadotropin receptor (LCGR) orluteinizing hormone receptor (LHR), is atransmembrane receptor found predominantly in theovary andtestis, but also many extragonadal organs such as theuterus andbreasts. The receptor interacts with bothluteinizing hormone (LH) and chorionic gonadotropins (such ashCG in humans) and represents aG protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning during reproduction.
Thegene for the LHCGR is found onchromosome 2 p21 in humans, close to theFSH receptor gene. It consists of 70 kbp (versus 54 kpb for the FSHR).[5] The gene is similar to the gene for the FSH receptor and the TSH receptor.
The LHCGR consists of 674 amino acids and has a molecular mass of about 85–95 kDA based on the extent of glycosylation.[6]
Like other GPCRs, the LHCG receptor possess seven membrane-spanning domains ortransmembrane helices.[7] The extracellular domain of the receptor is heavilyglycosylated. These transmembrane domains contain two highly conservedcysteine residues, which builddisulfide bonds to stabilize the receptor structure. The transmembrane part is highly homologous with other members of the rhodopsin family of GPCRs.[8] The C-terminal domain is intracellular and brief, rich inserine andthreonine residues for possiblephosphorylation.
Upon binding of LH to the external part of the membrane spanning receptor, atransduction of the signal takes place. This process results in the activation of aheterotrimeric G protein. Binding of LH to the receptor shifts itsconformation. The activated receptor promotes the binding ofGTP 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 bindsadenylate cyclase and activates thecAMP system.[9]
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.
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 ofcyclic AMP (cAMP). Cyclin AMP-dependent protein kinases are present astetramers 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 byphosphodiesterase and release 5’AMP. One of the targets of protein kinase A is the Cyclic AMP Response Element Binding Protein,CREB, which bindsDNA in thecell nucleus via direct interactions with specific DNA sequences calledcyclic AMP response elements (CRE); this process results in the activation or inactivation ofgene transcription.[5]
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified byprostaglandins. Other cellular regulators that participate are the intracellular calcium concentration regulated byphospholipase C activation,nitric oxide, and other growth factors.
Other pathways of signaling exist for the LHCGR.[6]
Luteinizing hormone up-regulates cholesterol side chain cleaving enzyme in sensitive tissues, the first step of all human steroidogenesis.
The LHCG receptor's main function is the regulation ofsteroidogenesis. This is accomplished by increasing the intracellular levels of the enzymecholesterol side chain cleaving enzyme, a member of thecytochrome P450 family. This leads to increased conversion of cholesterol into androgen precursors required to make many steroid hormones, including testosterone and estrogens.[10]
In the ovary, the LHCG receptor is necessary for follicular maturation and ovulation, as well as luteal function. Its expression requires appropriate hormonal stimulation byFSH andestradiol. The LHCGR is present ongranulosa cells,theca cells,luteal cells, and interstitial cells[6] The LCGR is restimulated by increasing levels ofchorionic gonadotropins in case apregnancy is developing. In turn, luteal function is prolonged and the endocrine milieu is supportive of the nascent pregnancy.
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.
Upregulation refers to the increase in the number of receptor sites on the membrane. Estrogen and FSH upregulate LHCGR sites in preparation forovulation. After ovulation, the luteinized ovary maintains LHCGR s that allow activation in case there is an implantation. Upregulation in males requires gene transcription to synthesize LH receptors within the cell cytoplasm. Some reasons as to why downregulated LH receptors are not upregulated are: lack of gene transcription, lack of RNA to protein conversion and lack of cell membrane targeted shipments from Golgi.
The LHCGRs become desensitized when exposed to LH for some time. A key reaction of this downregulation is thephosphorylation of the intracellular (orcytoplasmic) receptor domain byprotein kinases. This process uncouples Gs protein from the LHCGR.
Downregulation refers to the decrease in the number of receptor molecules. This is usually the result of receptorendocytosis. In this process, the bound LCGR-hormone complex bindsarrestin and concentrates inclathrin coated pits. Clathrin coated pits recruitdynamin and pinch off from the cell surface, becomingclathrin-coated vesicles. Clathrin-coated vesicles are processed intoendosomes, some of which are recycled to the cell surface while others are targeted tolysosomes. Receptors targeted to lysosomes are degraded. Use of long-acting agonists will downregulate the receptor population by promoting their endocytosis.
In 2019, the discovery of potent, and selective antagonists of the Luteinizing Hormone Receptor (BAY-298 and BAY-899) were reported which were able to reduce sex hormone levelsin vivo.[11] The latter fulfils the quality criteria for a 'Donated Chemical Probe' as defined by theStructural Genomics Consortium.[12]
A series of thienopyr(im)idine-based compounds[13] leading to optimized Org 43553 were described as the first Luteinizing Hormone Receptor agonists.[14][15]
Loss-of-function mutations in females can lead toinfertility. In 46, XY individuals severe inactivation can cause malepseudohermaphroditism, as fetal Leydig cells during may not respond and thus interfere with masculinization.[16] Less severe inactivation can result inhypospadias or amicropenis.[6]
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^Dufau ML, Cigorraga S, Baukal AJ, Sorrell S, Bator JM, Neubauer JF, et al. (December 1979). "Androgen biosynthesis in Leydig cells after testicular desensitization by luteinizing hormone-releasing hormone and human chorionic gonadotropin".Endocrinology.105 (6):1314–1321.doi:10.1210/endo-105-6-1314.PMID227658.
^van Straten NC, Schoonus-Gerritsma GG, van Someren RG, Draaijer J, Adang AE, Timmers CM, et al. (October 2002). "The first orally active low molecular weight agonists for the LH receptor: thienopyr(im)idines with therapeutic potential for ovulation induction".ChemBioChem.3 (10):1023–1026.doi:10.1002/1439-7633(20021004)3:10<1023::AID-CBIC1023>3.0.CO;2-9.PMID12362369.S2CID8732411.
^Heitman LH, Oosterom J, Bonger KM, Timmers CM, Wiegerinck PH, Ijzerman AP (February 2008). "[3H]Org 43553, the first low-molecular-weight agonistic and allosteric radioligand for the human luteinizing hormone receptor".Molecular Pharmacology.73 (2):518–524.doi:10.1124/mol.107.039875.hdl:1887/3209412.PMID17989351.S2CID34584880.
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"Glycoprotein Hormone Receptors: LH".IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived fromthe original on 2021-01-18. Retrieved2006-07-20.
