The gonadotrophin receptors: insights from the cloning of their cDNAs

Abstract

The cloning and expression of the cDNA's for the gonadotrophin hormone receptors has confirmed that these receptors are each composed of a single polypeptide which can both bind hormone and activate adenylyl cyclase when occupied with agonist. Although some studies by others have suggested that the LH/CG receptor and the FSH receptor are composed of multiple subunits (Ascoli and Segaloff 1989; Reichert and Dattatreyamurty 1989; Shin and Ji 1985a, b, and c; Smith et al. 1985; Smith et al. 1986), biochemical studies on the LH/CG receptor have shown that it is composed of a single polypeptide with a molecular weight of 93,000 when analyzed on sodium dodecyl sulfate gels in the presence or absence of disulfide reducing agents (Ascoli and Segaloff 1989). As the LH/CG receptor has been shown to be readily proteolyzed into smaller-sized fragments (Ascoli and Segaloff 1986; Ascoli and Segaloff 1989), it is reasonable to postulate that the FSH receptor may be similarly susceptible to proteolysis, and that this may account for the discrepant reports on its structure. Clearly, the molecular cloning and functional expression of the cDNA's for the rat ovarian LH/CG receptor (McFarland et al. 1989) and the rat testicular receptor (Sprengel et al. 1990) demonstrate conclusively that the gonadotrophin receptors are indeed single polypeptides. As shown schematically in Fig. 5.12, the gonadotrophin hormone receptors (together with the thyrotrophin receptor, see Frazier et al. 1990; Libert et al. 1989; Nagayami et al. 1989; Parmentier et al. 1989) define a unique subclass of G protein-coupled receptors. Thus, in addition to the seven membrane-spanning domains which appear to be the hallmark of G protein-coupled receptors, the gonadotrophin receptors (and thyrotrophin receptor) also contain large extracellular domains. These extracellular domains are composed of a repeating leucine-rich motif which is found in a number of widely-diverse proteins, collectively termed leucine-rich glycoproteins. We have shown that the extracellular domain of the LH/CG receptor is entirely responsible for binding hormone with high affinity. This is in contrast to the rhodopsin-like G protein-coupled receptors which have relatively small amino-terminal extracellular domains and in which the ligands interact directly with amino acids within the transmembrane helices. As with other G protein-coupled receptors, however, it is thought that the gonadotrophin receptors interact with and activate Gs through residues located within the cytoplasmic loops and the amino-terminal region of the cytoplasmic tail.(ABSTRACT TRUNCATED AT 400 WORDS)