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

人精子钾通道的分子特性及其在男性生育力中的作用

• 批准号: 9043907
• 负责人: Polina V Lishko
• 金额: $ 40.33万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043907
• 关键词: Acrosome Reaction; Alkalinization; Behavior; Binding; Biological Assay; Calcium; Calcium Channel; Cardiovascular Diseases; CatSper; Cell membrane; Cell physiology; Chemotaxis; Cholesterol; Code; Competence; Complex; Contraceptive methods; Data; Development; Diagnostic; Diagnostic tests; Electrophysiology (science); Enrollment; Epilepsy; Erectile dysfunction; Estrogens; Female; Fertility; Fertilization; Genes; Genetic screening method; Genomic DNA; Glucocorticoids; Health; Homeostasis; Hormones; Human; Human Characteristics; Incontinence; Infertility; Ion Channel; Knowledge; Lead; Libraries; Light; Link; Lipids; Male Contraceptive Agents; Male Infertility; Membrane; Membrane Potentials; Molecular; Mus; Mutate; Mutation; Oocytes; Outcome; Paroxysmal Dyskinesias; Patients; Pharmacology; Physiological; Physiology; Play; Potassium; Potassium Channel; Progesterone; Property; Protein Isoforms; Proteins; Protons; RNA Splicing; Recombinants; Regulation; Research; Role; Signal Pathway; Sperm Capacitation; Sperm Motility; Steroids; System; Testing; Tissues; Travel; base; cell motility; egg; exome; improved; infertility treatment; male; novel diagnostics; reconstitution; reproductive tract; sperm cell

 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.

 描述(申请人提供)：男性不育症是一个严重的问题，占全球不育病例的一半。至少50%的男性不育病例是 被认为是特发性的。我们对男性不育认识的巨大差距部分归因于我们对人类精子细胞生理学知识的不足，以及人类精子离子通道的未知身份。离子通道对精子生理来说是不可或缺的：它们调节精子的运动、对卵子的趋化和顶体反应。哺乳动物精子在通过女性生殖道时获得了使卵母细胞受精的能力。这一过程被称为获能，伴随着：1)通过质子通道的质子挤出引起的精子细胞内碱化；2)通过钙离子通道的钙内流引起的细胞内[Ca~(2+)]升高；以及3)K+外流引起的膜超极化。人类精子的质子通道和钙通道被鉴定为Hv1和CatSper，而人类精子的主要钾通道(HKSper)尚不清楚。钾通道是正常精子生理所必需的，因为它们调节细胞膜电位和细胞运动。在小鼠中，由KCNU1基因编码的pH敏感的精子K+通道受细胞内碱化调节，对男性生育能力是必不可少的。人类精子的K+通道具有相似的分子同一性，这一假设从未得到证实。根据我们的初步数据，情况并非如此，hKSper可能具有不同的分子同一性。本项目将揭示人类精子钾通道的精确分子同一性，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空白，将有助于识别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诊断测试，并揭示新的避孕目标。