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

描述(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结合在一起，创造出一个新的个体。对于人类，就像所有哺乳动物一样，精子必须到达卵子，穿透卵子的保护层，与卵细胞膜融合，并传递其遗传物质。我们已经确定了精子中的离子通道，但其他组织中没有。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，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的、碱激活的、钙选择性的离子通道，专门定位于精子尾巴的主要部分。4个CatSper基因中任何一个发生零突变的雄性小鼠是不育的，但在其他方面是完全正常的。CatSper空精子无法获得高度激活的运动能力，并降低了精子的耐受性。缺乏这些基因的雌性小鼠看起来完全正常，生育能力也正常。CatSper蛋白横跨精子尾部的质膜，因此其胞外表面可被小分子访问。这项提议的目的是开发高通量和二次验证筛查，以确定阻止CatSper活性的药物。CatSper阻滞剂应该容易地接触到精子外表面的结合部位，从而防止受精。由于CatSper只在成熟精子中表达，因此特定的阻断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。 公众意义：我们的目标是开发一种有效和安全的男性避孕药。该药物将针对成熟精子细胞表面一种名为CatSper的独特蛋白质。猫是男性生育所必需的。由于这种蛋白质只存在于成熟的精子中，因此抑制这种分子的药物应该不会对正常的睾丸或精子发育产生影响，也不会对男性或女性体内的其他器官产生影响。

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.