The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm
The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm
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DOI：
10.1038/nature09769
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发表时间：
2011-03-17
期刊：
影响因子：
64.8
通讯作者：
Kaupp, U. Benjamin
中科院分区：
文献类型：
--
作者：
Struenker, Timo;Goodwin, Normann;Kaupp, U. Benjamin
在输卵管中，围绕卵母细胞的卵丘细胞释放孕酮。在人类精子中，黄体酮通过非基因组机制刺激钙离子增加(1-3)。钙信号被认为控制精子的趋化、过度激活和顶体胞吐(4-8)。然而，潜在的信号机制一直是个谜。在这里，我们展示了黄体酮激活精子特异性的、pH敏感的CatSper钙通道(9-11)。我们发现黄体酮和碱性pH都刺激钙离子快速内流，几乎没有潜伏期，这与涉及代谢性受体和第二信使的信号通路不相容。钙-v通道阻断剂NNC55-0396和米贝拉地尔可抑制碱性pH和孕酮引起的钙信号。来自精子的膜片钳记录显示，一价和二价离子携带的碱性激活电流表现出精子特异性CatSper钙通道(10，11)的所有特征。黄体酮显著增强CatSper电流。碱性和黄体酮激活的CatSper电流都被这两种药物抑制。我们的结果解决了关于非基因组孕激素信号的长期争议。在人类精子中，CatSper通道本身或相关蛋白充当非基因组孕激素受体。CatSper通道阻滞剂的发现将极大地促进精子中钙信号的研究，并有助于进一步确定孕酮和CatSper的生理作用。
In the oviduct, cumulus cells that surround the oocyte release progesterone. In human sperm, progesterone stimulates a Ca2+ increase by a non-genomic mechanism(1-3). The Ca2+ signal has been proposed to control chemotaxis, hyperactivation and acrosomal exocytosis of sperm(4-8). However, the underlying signalling mechanism has remained mysterious. Here we show that progesterone activates the sperm-specific, pH-sensitive CatSper Ca2+ channel(9-11). 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 Ca-v 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+ channels(10,11). 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.