《自然》封面：精子的“秘密武器”

　　

生物通报道：在本期（3月24日）Nature杂志上，来自德国和美国的两个独立的研究小组发现孕酮能够强力激发精子鞭毛上的主要钙离子通道：CatSper，从而使其鞭毛摆动加快，在角逐的这场竞赛中取得胜利，这就是精子的“秘密武器”。这些研究成果公布在Nature封面上（见下图）。

女性体内的类固醇激素：黄体酮是由卵巢和胎盘产生的，这种激素能通过孕酮受体(progesteronere ceptor,pr)来支持受孕和胚胎形成。而另一种孕酮，由卵子周围的细胞释放的孕酮也在输卵管内刺激精子细胞，增强它们使卵子受精的能力，而孕酮这种作用的机制一直不清楚。

来自加州大学旧金山分校的研究人员以“Progesterone activates the principal Ca2+ channel of human sperm”为题，报道了孕酮增强精子能力的机制，他们发现孕酮能够强力激发精子鞭毛上的主要钙离子通道：CatSper，Catsper是近来发现的一类仅存于精子鞭毛上的阳离子通道，能作为Ca^2＋内流的通道参与精子超活化过程。

研究人员利用膜片钳技术分析了人类成熟精子，结果发现纳摩尔浓度的孕酮就能显著提高CatSper的通道能力，这证明了孕酮和CatSper在精子中的生理作用，这一原理还可用于新型非激素类避孕药的研发。

另外来自德国马普研究所的研究人员也确认了孕酮在激发精子鞭毛上的CatSper的功能，研究数据表明CatSper通道也许扮演了一种新型孕酮受体的角色，能调控孕酮在精子质膜层面上快速的、非基因组性质的效应。具体而言，CatSper收到孕酮信号后，就与孕酮结合，通道打开，这样钙离子就可以进入精子内，从而引发鞭毛摆动加快。孕酮是从卵子周围释放出来的，因此随着孕酮的扩散，这种信号就形成一个浓度梯度，精子通过CatSper接收信号，越靠近卵子，游动越快，最后到达卵子，与卵子融合。

这项研究不仅揭示了精子内动力的生理机制，而且有助于实现避孕，可以用于新型非激素类避孕药的研发。

近期还有另外一则避孕药相关的新闻：美国FDA批准了一种紧急避孕药：Ella，这是一种黄体酮受体阻断剂/拮抗剂，其主要作用是抑制或延迟女性排卵，2009年已在欧洲上市，商品名为EllaONe。

向FDA提交的临床试验数据来自于以下两项试验：
一项在美国40个计划生育诊所中实施的前瞻性、多中心、开放、单臂临床试验，共纳入18-35岁的妇女1242名，这些受试者均在无防护房事或避孕失败后48-120小时内服用Ella，整个试验中共有27人怀孕，占总人数的2.2%。

另一项在美国、英国和爱尔兰进行的随机、多中心、单盲、阳性对照临床试验，844名妇女0-120小时内服用Ella，其中1.9%的受试者怀孕。在本试验中有10%的受试者服用Ella的时间是房事后72小时，这些人中无一人怀孕。

临床试验中观察到Ella最常见的不良反应包括：头痛，恶心，腹痛，疼痛/不适、月经期间痛经，疲劳，头晕，不良反应类似美国FDA已批准的左炔诺孕酮紧急避孕药（Plan B）。FDA称，作为紧急避孕药，Ella的上市申请提供了令人信服的有效性证据和充分的安全性信息。

（生物通：万纹）

原文摘要：

The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm

In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca2+ increase by a non-genomic mechanism1, 2, 3. The Ca2+ signal has been proposed to control chemotaxis, hyperactivation and acrosomal exocytosis of sperm4, 5, 6, 7, 8. However, the underlying signalling mechanism has remained mysterious. Here we show that progesterone activates the sperm-specific, pH-sensitive CatSper Ca2+ channel9, 10, 11. We found that both progesterone and alkaline pH stimulate a rapid Ca2+ influx with almost no latency, incompatible with a signalling pathway involving metabotropic receptors and second messengers. The Ca2+ signals evoked by alkaline pH and progesterone are inhibited by the Cav channel blockers NNC 55-0396 and mibefradil. Patch-clamp recordings from sperm reveal an alkaline-activated current carried by mono- and divalent ions that exhibits all the hallmarks of sperm-specific CatSper Ca2+ channels10, 11. Progesterone substantially enhances the CatSper current. The alkaline- and progesterone-activated CatSper current is inhibited by both drugs. Our results resolve a long-standing controversy over the non-genomic progesterone signalling. In human sperm, either the CatSper channel itself or an associated protein serves as the non-genomic progesterone receptor. The identification of CatSper channel blockers will greatly facilitate the study of Ca2+ signalling in sperm and help to define further the physiological role of progesterone and CatSper.

Progesterone activates the principal Ca2+ channel of human sperm

Steroid hormone progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg’s protective vestments1. Progesterone induces Ca2+ influx into spermatozoa1, 2, 3 and triggers multiple Ca2+-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg4, 5, 6, 7, 8. As an ovarian hormone, progesterone acts by regulating gene expression through a well-characterized progesterone nuclear receptor9. However, the effect of progesterone upon transcriptionally silent spermatozoa remains unexplained and is believed to be mediated by a specialized, non-genomic membrane progesterone receptor5, 10. The identity of this non-genomic progesterone receptor and the mechanism by which it causes Ca2+ entry remain fundamental unresolved questions in human reproduction. Here we elucidate the mechanism of the non-genomic action of progesterone on human spermatozoa by identifying the Ca2+ channel activated by progesterone. By applying the patch-clamp technique to mature human spermatozoa, we found that nanomolar concentrations of progesterone dramatically potentiate CatSper, a pH-dependent Ca2+ channel of the sperm flagellum. We demonstrate that human CatSper is synergistically activated by elevation of intracellular pH and extracellular progesterone. Interestingly, human CatSper can be further potentiated by prostaglandins, but apparently through a binding site other than that of progesterone. Because our experimental conditions did not support second messenger signalling, CatSper or a directly associated protein serves as the elusive non-genomic progesterone receptor of sperm. Given that the CatSper-associated progesterone receptor is sperm specific and structurally different from the genomic progesterone receptor, it represents a promising target for the development of a new class of non-hormonal contraceptives.