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

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1) The luteinizing hormone receptor (LHR) is a member of the subfamily of glycoprotein hormone receptors within the G protein-coupled receptor (GPCR)/7-transmembrane domain superfamily. Major advances have been made in determining the structure-function properties of the LHR and its gene. The hormone binding region was localized to N-terminal exons of the extracellular domain (exons 1-7) where 4 cys in exon 1 are essential for hormone binding, and other two Cys (exon 5 and 6) lie within the leucine repeat (exon 2-8) pocket structure derived from leucine-rich ribonuclease inhibitor. Mutations or insertion in the LHR of corresponding amino acids from the FSH receptor demonstrated that the leucine-rich repeat at Leu29 (Leu29Glu) is essential for hormone binding, and that insertion or deletion of leucine zippers in exons 1-4 greatly reduced binding. These changes caused pertubation of structure with consequent abolition/or reduction of LHR interaction sites. Other studies provided evidence for the presence of at least two human LHR genes in the human genome. The isolated genomic clone (Gene II) conforms with the sequence of the human ovarian cDNA and differs from another isolated gene (Gene I) in its coding (exon 1) and 5' flanking region. The promoter domain of this Tataless non-initiator class gene (Gene II) contains two Sp1 sites of central importance to transcription, and functional inhibitory elements at an AP2 element and ERE-half site (non-ER dependent) and cAMP modulation (non-ERE or AP2 dependent). The findings suggest that differential promoter activity and expression of LHR cDNAs may be linked to gene diversity. 2) Prolactin is the most diversified pituitary hormone with important functions in reproduction and lactation. The expression of the prolactin receptor is under the control of two tissue-specific promoters, PI, gonads and PII, liver and a common tissue promoter, PIII, which is the sole functional promoter in the mammary gland. Studies on the mechanisms of gonad-specific localization demonstrated an essential role for steroidogenic factor-1 (SF1) expressed in gonads and pituitary gland, in transcriptional activation of promoter I of the prolactin receptor gene. This finding explains the tissue-specific expression of PI in the gonads but not in liver and the mammary gland. 3) Studies on the regulation of androgen synthesis focused on the requirements for activation of 17beta-hydroxysteroid dehydrogenase in the Leydig cell (androstenedione to testosterone). This enzyme requires a viable glucose transport system for optimal activity and a high-energy phosphate was discovered to be the requisite product of glucose metabolism for its activation. The ATP requirement for modulation of the affinity of the enzyme for androstenedione appears to be related to the participation of protein kinase A and calmodulin kinases.