CarSpers:sperm-specific ion channels; targets for male contraceptives

描述（由申请人提供）：精子和卵子的融合导致父亲和母亲的遗传信息的结合，创造一个新的个体。人类和所有哺乳动物一样，精子必须到达卵子，穿透其保护层，与卵母细胞膜融合，并传递其遗传物质。我们已经在精子中发现了离子通道，但在其他组织中却没有。CatSpers1-4（精子阳离子通道）是存在于包括人类在内的所有哺乳动物中的4个不同的基因，它们编码6个跨膜离子通道蛋白亚基。这些蛋白质形成了精子特异性的、碱激活的、钙选择性的离子通道，只定位于精子尾部的主要部分。4种CatSper基因中任何一种的零突变纯合的雄性小鼠是不育的，但其他方面完全正常。无精子不能获得过度激活的运动能力，精子耐力降低。缺乏这些基因的雌鼠看起来完全正常，生育能力也正常。CatSper蛋白横跨精子尾部的质膜，因此小分子可以进入其细胞外表面。该提案的目的是开发高通量和二次验证筛选，以识别阻断CatSper活性的药物。CatSper阻滞剂应该能很容易地进入精子外表面的结合位点，从而阻止受精。由于CatSper仅在成熟精子中表达，因此特定的阻滞剂应该对其他细胞和组织、睾丸功能或精子发育没有副作用。

DESCRIPTION (provided by applicant): The fusion of sperm and egg lead to the combination of the father's and mother's genetic information to create a new individual. In humans, as in all mammals, sperm must reach the egg, penetrate its protective coat, fuse with the oocyte membrane, and deliver its genetic material. We have identified ion channels that are in spermatozoa, but not other tissues. CatSpers1-4 (Cation channel of Sperm) are 4 distinct genes present in all mammals, including humans, that encode 6 transmembrane-spanning ion channel protein subunits. These proteins form a sperm-specific, alkaline-activated, calcium-selective ion channel localized exclusively to the principal piece of the sperm tail. Male mice homozygous for null-mutations of any of the 4 CatSper genes are infertile but otherwise are completely normal. CatSper null sperm are unable to acquire hyperactivated motility and have reduced sperm endurance. Female mice lacking these genes appear completely normal, and have normal fertility. The CatSper protein spans the plasma membrane of the spermatozoan tail, and thus its extracellular surface is accessible to small molecules. The purpose of this proposal is to develop high throughput, and secondary verification screens, to identify drugs that block CatSper activity. A CatSper blocker should readily access binding sites on the external surface of sperm and thus prevent fertilization. Since CatSper is only expressed in mature sperm, a specific blocker should have no side effects on other cells and tissues, testicular function, or sperm development. PUBLIC RELEVANCE: We aim to develop an effective and safe male contraceptive. The drug will be targeted against a unique protein on the surface of mature sperm cells, called CatSper. CatSper is required for male fertility. Since the protein is only present on mature sperm, a drug inhibiting this molecule should have no effect on normal testicular or sperm development, and no effect on other organs within males or females.