MECHANISM OF ACTION OF PEPTIDE HORMONES IN STEROIDOGENIC CELLS

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Cytochrome P450(17-alpha) is an important component of the steroidogenic pathway leading to the production of androgen within the testis and ovary. This microsomal enzyme catalyzes two consecutive oxidation reactions. Site-directed mutagenesis studies of amino acid residues of the conserved region between P450(17-alpha), P45O(c2l) and the progesterone receptor have elucidated structures responsible for the activities of 17-alpha- hydroxylase and 17,20 desmolase. The substitution of Arg346 to alanine differentially abolished lyase activity without affecting hydroxylase activity with accumulation of the 17-alpha-hydroxylated intermediate, while mutations at the Arg361 position resulted in total loss of hydroxylase activity. These findings are consistent with both a common steroid-binding site during the course of two reactions of C3 to Arg361 region and a point of interaction of the hydroxylated intermediate at the hydroxyl group of Arg346, and reveal the potential for separation of the two activities by chemical and biological modulators within the active site region of P450(17-alpha). Several peptide hormones produced in the Leydig cell, including neuropeptides, act through specific cell surface receptors to modulate the actions of LH on steroidogenesis. Recent studies have demonstrated that CRF secreted from the Leydig cells acts as a potent autocrine negative regulator of gonadotropin action and consequently of androgen production. The secretion of CRF by the Leydig cell is stimulated by LH via initial release of serotonin and autocrine activation of 5HT2 receptors. Serotonin acts on 5HT2 receptors in the Leydig cell that are distinct from those of the brain to stimulate CRF secretion through a pertussis toxin insensitive G-protein. The actions of CRF in the Leydig cell were found to be mediated through the phosphoinositide system and protein kinase C activation, and serotonin presumably activates a similar signalling pathway. The diversity in the biochemical responses to CRF and 5HT2 receptor activation (i.e., inhibition of adenylate cyclase at the cytoplasmic aspect of the cell membrane vs. stimulation of CRF release from secretion granules) may reflect the stimulation of different protein kinase C isoenzymes. The secretion of CRF by the Leydig cell is stimulated by LH via initial release of 5HT and activation of 5HT2 receptors in the Leydig cell. The gonadotropin to 5HT to CRF inhibitory loop serves to continuously buffer the stimulation of androgen production by gonadotropin. 5HT, the immediate stimulus of testicular CRF secretion, is released during stress and is locally increased in the testis in pathological conditions associated with impaired testicular function (i.e., orchitis, varicocele). These basic studies on 5HT and CRF are relevant to the pathogenesis of testicular dysfunction in these states, and may have application in the development of antagonist therapies to block CRF production.