MECHANISM OF ACTION OF PEPTIDE HORMONES IN STEROIDOGENIC CELLS

细胞色素P450（17-α）是类固醇生成酶的重要组成部分。 导致睾丸和卵巢内产生雄激素的途径。 这种微粒体酶催化两个连续的氧化反应。 保守氨基酸残基的定点突变研究 P450（17-α），P450（c2 l）和孕酮受体之间的区域具有 阐明了负责17-α- 羟化酶和17，20碳链酶。 Arg 346取代为丙氨酸 差异消除裂解酶活性而不影响羟化酶 活性与17-α-羟基化中间体的积累，而 Arg 361位点的突变导致羟化酶的完全丧失 活动 这些发现与常见的类固醇结合 C3对Arg 361区域和一个点的两次反应过程中的位点 羟基化中间体在羟基上的相互作用 Arg 346，并揭示了分离两种活动的潜力， 活性部位区域内的化学和生物调节剂 P450（17-α）。 睾丸间质细胞产生的几种肽激素， 包括神经肽，通过特定的细胞表面受体起作用， 调节LH对类固醇生成的作用。 最近的研究 证明了从Leydig细胞分泌的CRF作为一种有效的 促性腺激素作用的自分泌负调节因子， 雄激素的产生 刺激间质细胞分泌CRF 通过LH通过5-羟色胺的初始释放和5 HT 2的自分泌激活 受体。 5-羟色胺作用于Leydig细胞中的5 HT 2受体， 与大脑不同的是， 百日咳毒素不敏感G蛋白。 CRF在睾丸间质细胞中的作用 发现细胞通过磷酸肌醇系统介导， 蛋白激酶C激活，血清素可能激活类似的 信号通路 CRF生化反应的多样性， 5 HT 2受体活化（即，腺苷酸环化酶的抑制作用 细胞膜的细胞质方面与刺激CRF从 分泌颗粒）可能反映了不同蛋白激酶的刺激 C同工酶。 LH刺激Leydig细胞分泌CRF 通过5 HT的初始释放和Leydig中5 HT 2受体的激活， cell. 促性腺激素-5-HT-CRF抑制环用于 持续缓冲促性腺激素对雄激素产生的刺激。 5 HT是睾丸CRF分泌的直接刺激物， 在病理条件下睾丸中局部增加 与睾丸功能受损相关（即，睾丸炎、精索静脉曲张）。 5-HT和CRF的这些基础研究与CRF的发病机制有关， 睾丸功能障碍在这些国家，并可能有应用， 开发拮抗剂疗法以阻断CRF产生。

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.