MECHANISM OF ACTION OF PEPTIDE HORMONES IN STEROIDOGENIC CELLS

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This project examines the actions of gonadotropins on steroid biosynthesis and secretion in Leydig cells. We are performing structure-function studies of cytochrome P450-17alpha (CYP17), the key enzyme for synthesis of androgen and glucocorticoids, which catalyses consecutive oxidation reactions at C-17 within delta4 or delta5 precursors to produce the 17alpha-hydroxylated intermediate (17alpha- hydroxylase) and androgens (17-20 lyase). Mutational analysis of rat CYP17 revealed that charged residues in the conserved domain between residues 343 and 363 contribute to lyase and hydroxylase activities. Arg346 is essential for both delta4 and delta5-lyase activities and Arg363 is involved in the hydroxylase reaction. We have also determined species-specific differences between rat and human/bovine/pig sequences for delta4 versus delta5-lyase activities (Phe343 rat vs Ileu343 human). Our findings emphasizing the physical separation of hydroxylase from lyase activity as well as the importance of domain 343-348 for lyase activity in CYP17 are relevant to the development of selective inhibitors of androgen formation for treatment of prostate cancer, and to the basis of certain forms of male pseudohermaphroditism. We also demonstrated that CRF acts as an antireproductive hormone in the testis and inhibits LH-induced signaling and androgen production. CRF exerts autocrine inhibitory actions in the Leydig cell, whence its secretion is stimulated by LH acting via a high-affinity 5HT2 serotonin receptor. A low-affinity 5HT2 autoreceptor is also present and exerts negative feedback regulation of 5HT release. Propranolol, an anti-hypertensive beta-adrenergic blocker that frequently causes impotence, simulates CRF secretion by its antagonist action of the serotonergic autoreceptor and inhibits LH-induced steroidogenesis in the Leydig cell.