Understanding sperm membrane roles in male fertility

哺乳动物精子头部的分子必须在与卵子相遇之前进行重组，以便使其受精。这种重组是由精子收到的信号开始的，这些信号导致精子重组头部的膜结构，并启动特定的内部反应，使精子能够与卵子结合并穿透卵子。信号的确切性质(S)以及它们是如何接收的尚不清楚，这使得提高男性的生育力或保存精子用于人工授精变得困难。一种名为Na/K-ATPase的分子是众所周知的一种酶，但最近在一些人体细胞中被认为是膜结合的信号受体。我们证明，它也作为膜受体在精子中发挥作用，当其特定的激素哇巴因与其结合时，向精子发送信号以开始获能。Na/K-ATPase由两个亚基组成，每个亚基都有几种亚型。想一想一个子单元台式机、笔记本电脑或iPad电脑的异构体，每种都需要稍微不同的方法来打开它们。另一个子单元是外围设备，可以是打印机、扫描仪或网络摄像头。将任何一个计算机亚型与任何一个外周亚型配对会影响配对设备的功能，当然也会改变其输出。同样，精子Na/K-ATPase中的异构体和亚基影响其功能，我们假设，良好的生育力实际上取决于拥有正确的一对异构体，才能使Na/K-ATPase作为信号受体发挥最佳作用，就像你需要配对正确的计算机和外围设备以平稳运行，并有效地产生你想要的高质量输出一样。由于亚基是蛋白质，而精子头部的膜首先与卵子结合并开始获能，在5年的研究中，我们将比较高生育力公牛和低生育力公牛精子头膜中亚基的特定氨基酸结构，以确定哪一种配对与最佳生育能力有关；是否是异构体的数量或其结构影响生育能力；我们将跟踪精子中最终允许受精的信号激活路径。这服务于长期目标，能够解释目前尚未解释的不育症原因，了解并能够更好地保护、预测和改善影响精子生育能力的精子膜分子。结果将使我们能够检测出生育机会较低的男性，并设计出保护这些关键精子膜分子的补救方法。这将提高家养和濒危物种的繁殖成功，并有可能在人类繁殖中找到应用。

The molecules in the head of mammalian sperm must reorganise just prior to meeting the egg, in order to fertilise it. This reorganisation is started by signals that the sperm receives that cause the sperm to reorganise the membrane structure of its head and start specific internal reactions that enable the sperm to bind to and penetrate the egg. The exact nature of the signal(s), and how they are received, is unknown, making it difficult to improve the fertility of the male or to preserve sperm for artificial insemination. One molecule, Na/K-ATPase, is well known as an enzyme but recently was recognised as a membrane-bound signal receptor in some body cells. We showed that it also acts in sperm as a membrane receptor, sending signals into the sperm to start capacitation when its specific hormone ouabain binds to it. Na/K-ATPase is made of two subunits, each of which has several isoforms. Think of the isoforms of one subunit desktop, laptop or ipad computer, each requiring somewhat different methods to turn them on. The other subunit is a peripheral device, either a printer, scanner or webcam. Pairing any one computer isoform with any one peripheral isoform affects the function of the paired devices, and certainly changes its output. Similarly, isoforms and subunits in sperm Na/K-ATPase affect how it functions, and we hypothesize that good fertility really depends on having the correct pair of isoforms to have Na/K-ATPase perform optimally as a signal-receptor, just as you need to pair the correct computer and peripheral device to function smoothly, and efficiently produce the high-quality output you want. Since the subunits are proteins, and it is the membrane over the head of the sperm that first binds to the egg and where capacitation starts, over the 5 years of the research we will compare the specific amino acid structure of the subunits in the head membrane of sperm from high- and low-fertility bulls to identify which pairing is associated with the best fertility; whether it is the amount of isoform, or its structure, that influences fertility; and we will follow the signal's activation path in the sperm that ultimately permits fertilization. This serves the long-term objective, to be able to explain currently unexplained causes of infertility, to understand and be able to better protect, predict and improve sperm membrane molecules that impact fertility of sperm. Results will enable us to detect males with poor chances of fertility, and to design remediation methods that will protect those critical sperm membrane molecules. This will enhance reproductive success for domestic and endangered species, and potentially find application in human reproduction.