GONADAL RECEPTORS/MECHANISMS OF ACTION OF PEPTIDE HORMONES IN STEROIDOGENIC CELLS

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1) The luteinizing hormone receptor is a seven transmembrane G protein-coupled receptor with a high-affinity hormone binding site located on its N-terminal extracellular domain. Mutational studies have identified two specific classes of extracellular cysteine residues that are required for surface expression or hormone binding. All four non-conserved cysteines from exon 1 are essential for binding activity and the conserved cysteines in exon 5 and 6 (109,134) are important for hormone binding. Disulfide bonding among cysteines in exon 1, and between those of exon 5 and 6, were indicated by these studies. All but two of the eight remaining cysteines, including those in loops 1 and 2 (exons 7-11) produced defects in receptor translocation to the cell surface but not in hormone binding. Thus, the requirement of cysteine in exon 1 for hormone binding activity is not related to processing of the nascent receptor. The exon 1 cysteines, in conjuction with the N-glucosamine residue of the glycosyl chains at Asn152 and Asn173, are required for refolding of the hormone binding domain of the denatured/reduced mature receptor to its active configuration. The sugar residues are required for stabilization/acquisition of the active conformation of the mature receptor and of the nascent receptor. 2) Isolation and structural characterization of the corticotropin-releasing hormone gene included the complete mapping of its intron/exon organization and the basis of the pituitary splice variants, and the isolation of novel spliced variants of the Leydig cell CRF receptor. These studies suggest that the differences in signal transduction between pituitary and Leydig cells are not attributable to the expression of different receptor isoforms. They also provide evidence for an evolutionary link between the intronless transmembrane/ cytoplasmic module of the glycoprotein receptors and the intron-containing module of the CRF receptor. 3) Unravelling the complex structure of the prolactin receptor gene has identified promoter regions and regulatory elements involved in transcriptional activation of the tissue-specific promoters (PI-PIII). The promoter utilized in the mammary gland has been identified. 4) CYP17, the key enzyme of the androgen pathway, was found to have species and tissue-specific differences in its regulatory sequences. Such differences in the amino acid domains required for hydroxylase activity within and between species (human/bovine vs. rat) are consistent with their differential regulation of lyase activity in steroidogenic cells.