Luteinizing hormone/choriogonadotropin receptor

Transmembrane receptor found in humans

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.

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). 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. Like other GPCRs, the LHCG receptor possess seven membrane spanning domains or transmembrane helices. 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. The C terminal domain is intracellular and brief, rich in serine and threonine residues for possible phosphorylation.

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. 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 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.

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 The latter fulfils the quality criteria for a 'Donated Chemical Probe' as defined by the Structural Genomics Consortium. A series of thienopyr(im)idine based compounds leading to optimized Org 43553 were described as the first Luteinizing Hormone Receptor agonists.

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. Less severe inactivation can result in hypospadias or a micropenis.