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 and
testis, but also many extragonadal organs such as the
uterus and
breasts. The receptor interacts with both
luteinizing hormone (LH) and chorionic gonadotropins (such as
hCG in humans) and represents a
G protein-coupled receptor (GPCR). Its activation is necessary for the hormonal functioning during reproduction.
LHCGR gene
The
gene for the LHCGR is found on
chromosome 2 p21 in humans, close to the
FSH 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.
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.[6]
Like other GPCRs, the LHCG receptor possess seven membrane-spanning domains or
transmembrane helices.[7] The extracellular domain of the receptor is heavily
glycosylated. These transmembrane domains contain two highly conserved
cysteine 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.[8] The C-terminal domain is intracellular and brief, rich in
serine and
threonine residues for possible
phosphorylation.
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 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.
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 (cAMP). Cyclin AMP-dependent protein kinases are present as
tetramers 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 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 via direct interactions with specific DNA sequences called
cyclic AMP response elements (CRE); this process results in the activation or inactivation of
gene transcription.[5]
The signal is amplified by the involvement of cAMP and the resulting phosphorylation. The process is modified by
prostaglandins. Other cellular regulators that participate are the intracellular calcium concentration regulated by
phospholipase C activation,
nitric oxide, and other growth factors.
Other pathways of signaling exist for the LHCGR.[6]
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 family. This leads to increased conversion of cholesterol into androgen precursors required to make many steroid hormones, including testosterone and estrogens.[10]
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,
theca cells,
luteal cells, and interstitial cells[6] The LCGR is restimulated by increasing levels of
chorionic gonadotropins in case a
pregnancy 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 for
ovulation. 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.
Desensitization
The LHCGRs become desensitized when exposed to LH 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 LHCGR.
Downregulation
Downregulation refers to the decrease in the number of receptor molecules. This is usually the result of receptor
endocytosis. In this process, the bound LCGR-hormone complex binds
arrestin and concentrates in
clathrin coated pits. Clathrin coated pits recruit
dynamin 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 antagonists and agonists
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 levels in vivo.[11] The latter fulfils the quality criteria for a 'Donated Chemical Probe' as defined by the
Structural 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]
LHCGR abnormalities
Loss-of-function mutations in females can lead to
infertility. In 46, XY individuals severe inactivation can cause male
pseudohermaphroditism, as fetal Leydig cells during may not respond and thus interfere with masculinization.[16] Less severe inactivation can result in
hypospadias or a
micropenis.[6]
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External links
"Glycoprotein Hormone Receptors: LH". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from
the original on 2021-01-18. Retrieved 2006-07-20.