Gonadotropin Receptors

Like their ligands, the gonadotropin receptors are structurally related glycoproteins, belonging to the large family of G protein-coupled receptors (GPCRs) (see Figs. 2 and 3) (8-10). They each have a transmembrane domain that traverses the plasma membrane

Carbohydrates Presentation Images

Fig. 1. Schematic presentation of sizes, locations of the carbohydrate side chains, and currently known mutations and polymorphisms in the gonadotropin subunits, i.e., common a-subunit (Ca), LHP, FSHP, and hCGp. The numbers below the right ends of the bars indicate the numbers of amino acids in the mature subunit proteins. Symbols "Y" and "O" indicate the locations of ^-linked and O-linked carbohydrate side chains, respectively. The arrows below the bars indicate the locations of point mutations and polymorphisms.

Fig. 1. Schematic presentation of sizes, locations of the carbohydrate side chains, and currently known mutations and polymorphisms in the gonadotropin subunits, i.e., common a-subunit (Ca), LHP, FSHP, and hCGp. The numbers below the right ends of the bars indicate the numbers of amino acids in the mature subunit proteins. Symbols "Y" and "O" indicate the locations of ^-linked and O-linked carbohydrate side chains, respectively. The arrows below the bars indicate the locations of point mutations and polymorphisms.

as seven a-helices connected by three extracellular and three intracellular loops. The glycoprotein hormone receptors form a subgroup within this gene family with a distinct long ^-terminal extracellular domain, comprising approximately half the size of the receptor. The C-termini of the receptor proteins form short intracellular tails. Whereas the FSH-R binds only FSH, LH and hCG are so structurally similar that they bind to the same LH-R. Both gonadotropin receptor genes are localized on chromosome 2p21 (11,12), and they carry considerable structural similarity, especially in their transmembrane domains. The clearest difference is that the first 10 exons encode the extracellular domain of LH-R, whereas this domain is encoded by 9 exons in the FSH-R. The last long eleventh exon in LH-R (tenth in FSH-R) encodes the transmembrane and intracellular domains.

Gonadotropins bind to the extracellular domain of their receptors. This domain contains several leucine-rich repeats that are found in various proteins responsible for protein-protein interactions. The domain is glycosylated in an ^-linked fashion, but the role of these structures in receptor function is not clear. The extracellular and transmembrane domains are connected by a short hinge region that may influence ligand specificity, as shown with a human mutation of LH-R lacking this region (13). The

Testosterone Levels
Fig. 2. Locations of the currently known mutations of the human luteinizing hormone receptor (LHR). □ inactivating mutation; •, activating mutation; *, polymorphism. The short lines across the peptide chain depict the exon boundaries.

transmembrane domain, with its seven membrane-spanning a-helices and intracellular and extracellular loops, resembles other GPCRs and is crucial for signal transduction. In particular, the third intracellular loop, the sixth transmembrane domain, and the cytoplasmic tail are closely involved in G protein coupling and signal transduction. The crystal structure of the gonadotropin receptors is not yet known.

The gonadotropin receptors are primarily coupled to a G protein that activates adenylyl cyclase and elevates intracellular cyclic adenosine monophosphate (cAMP) levels (8,10). These receptors also activate other signaling pathways, including phos-phatidylinositide turnover, intracellular Ca2+, mitogen-activated protein kinases, and activation of the Gi protein (8,10,14). The alternate signaling pathways are often activated at higher hormone concentrations, and their functions may be limited to special conditions in which gonadotropin levels are elevated, e.g., pregnancy or constitutively activating receptor mutations (see section on activating mutations).

Testosterone Levels

Fig. 3. Locations of the currently known mutations of the human follicle-stimulating hormone receptor (FSH-R). □, inactivating mutation; •, activating mutation; *, polymorphism. The short lines across the peptide chain depict the exon boundaries. The Asn191Ile FSHR mutation has been found only in a heterozygous form in a normal subject. The activating Asp567Gly mutation has marginal constitutive activity in vitro.

Fig. 3. Locations of the currently known mutations of the human follicle-stimulating hormone receptor (FSH-R). □, inactivating mutation; •, activating mutation; *, polymorphism. The short lines across the peptide chain depict the exon boundaries. The Asn191Ile FSHR mutation has been found only in a heterozygous form in a normal subject. The activating Asp567Gly mutation has marginal constitutive activity in vitro.

The transcription of the gonadotropin receptors is characterized by a complex phenomenon of alternative splicing and several mRNA species; messages that are both shorter and longer than the one deduced from the expected translation product are observed (8,10). Both inhibitory and stimulatory interactions with the full-length receptors have been proposed for these putative receptor variants. However, no clear physiological or pathophysiological role for them has yet been demonstrated.

Invisible Viagara

Invisible Viagara

You are about to discover the "little-known" techniques, tricks and "mind tools" that will show you how to easily "program" your body and mind to produce an instant, rock-hard erection. Learn how to enjoy all of the control, confidence and satisfaction that comes from knowing you can always "rise to the challenge" ... and never have to deal with embarrassment, apologies, shyness or performance anxiety in the bedroom, ever again.

Get My Free Ebook


Post a comment