Molecular identity of human sperm potassium channel and its role in male fertility

 描述（由申请人提供）：男性不育是一个严重的问题，占全球所有不育病例的一半。至少50%的男性不育病例是 被认为是特发性的。我们对男性不育症的理解存在巨大差距，部分原因是我们对人类精子细胞生理学的认识不足，以及人类精子离子通道的身份不明。离子通道是精子生理学中不可缺少的：它们调节精子的运动性、对卵子的趋化性和顶体反应。哺乳动物精子在通过雌性生殖道时获得使卵母细胞受精的能力。这种进展被称为获能，并伴有：1）精子细胞内碱化，由质子通过质子通道挤出引起; 2）细胞内[Ca 2 +]升高，由钙离子通过钙离子通道流入引起; 3）膜超极化，由K+流出引起。虽然人类精子的质子和钙通道被鉴定为Hv 1和CatSper，但人类精子的主要钾通道（hKSper）尚不清楚。钾离子通道是精子正常生理所不可缺少的，因为它们调节细胞膜电位和细胞运动。在小鼠中，由KCNU 1基因编码的pH敏感性精子K+通道受细胞内碱化调节，对雄性生育力至关重要。人们一直认为，但从未被证明，人类精子的K+通道具有相似的分子特性。根据我们的初步数据，情况并非如此，并且hKSper可能具有不同的分子身份。该项目将揭示人类精子钾通道的精确分子身份，研究该通道的调控，并解释钾通道在人类精子发育、成熟和受精过程中的作用。从拟议的研究中获得的知识将填补我们对人类精子发育基本机制的理解中的空白，将有助于确定精子细胞中钾稳态所必需的分子，将导致创建新的男性生育力诊断测试，并揭示新的避孕目标。

 DESCRIPTION (provided by applicant): Male infertility constitutes a serious problem contributing to half of all infertility cases worldwide. At least 50% of male infertility cases are considered idiopathic. This huge gap in our understanding of male infertility is partially attributd to our insufficient knowledge of human sperm cell physiology and to the unknown identity of human sperm ion channels. Ion channels are indispensable for sperm physiology: they regulate sperm motility, chemotaxis toward the egg and the acrosome reaction. Mammalian spermatozoa gain competence to fertilize an oocyte as they travel through the female genital tract. This progression is termed capacitation and is accompanied by: 1) sperm intracellular alkalinization, evoked by proton extrusion through proton channels; 2) elevation of the intracellular [Ca2+], evoked by calcium influx through calcium ion channels, and 3) membrane hyperpolarization that is evoked by K+ efflux. Whereas the proton and calcium channels of human sperm are identified as Hv1 and CatSper, the principal potassium channel of human sperm (hKSper) is unknown. Potassium channels are indispensable for normal sperm physiology since they regulate cell membrane potential and cell motility. In mice, pH-sensitive sperm K+ channel, coded by the KCNU1 gene is regulated by intracellular alkalinization and is essential for male fertility. It has been assumed, but never been proven that the K+ channel of human sperm has similar molecular identity. According to our preliminary data it is not the case, and hKSper likely has different molecular identity. This project will reveal the precise molecular identity of human sperm potassium channel, will study the regulation of this channel, and explain the role of potassium channels during human sperm development, maturation and fertilization. The knowledge gained from the proposed research will fill in gaps in our understanding of the basic mechanisms underlying the development of human sperm, will help to identify the molecules essential for potassium homeostasis in sperm cells, will lead to the creation of novel diagnostic tests for male fertility, and reveal new targets for contraception.