Membrane-based signalling pathways controlling sperm capacitation and fertility

哺乳动物精子中的分子在与卵子相遇之前必须重组，以使其受精。这种重组是由精子接收到的信号启动的，这些信号导致精子改变其膜并启动特定的内部反应，使其能够结合并穿透卵子。这些信号的确切性质以及它们是如何被接收的，是未知的，这使得很难提高男性的生育能力，或者保存精子进行人工授精。Na/K-ATP酶是一种众所周知的酶，它可以使离子穿过许多细胞类型的膜，最近被认为是一些体细胞中的膜结合信号受体。我们发现，它在精子中也以这种方式起作用，就像膜受体对特定激素的反应一样。在其他细胞上刺激它的激素是类固醇分子哇巴因。 Na/K-ATP酶由亚基组成，每个亚基有几种亚型。把一个子单元想象成一台电脑，有台式机、笔记本电脑或iPad，每一个都需要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。将任何一个计算机异构体与任何一个外围设备异构体配对都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-ATP酶的亚型和亚基影响它的功能（作为酶或受体），以及它是否可以运输离子或启动细胞内信号。我们建议确定特定的亚基，当配对在一起，是一个积极的信号受体。我们将确定这些亚基的特定氨基酸结构。由于哇巴因和孕酮都是受精时存在于雌性体内的类固醇，我们将确定它们是否以及如何相互作用以控制Na/K-ATP酶的作用。我们还将确定ATP酶周围的其他膜分子如何影响其功能（您的计算机是在办公室还是飞机上？）。这些知识将有助于我们保护，预测和改善ATP酶功能和精子生育力的家庭和濒危物种，并可能在人类生殖。

The molecules in 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 which cause the sperm to change its membrane and start specific internal reactions that enable it 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 that moves ions across the membranes of many cell types, and recently has been recognised as a membrane-bound signal receptor in some body cells. We showed that it also acts this way in the sperm, reacting as a membrane receptor does to the presence of a specific hormone. The hormone which stimulates it on other cells is the steroid molecule ouabain. Na/K-ATPase is made of subunits, each of which has several isoforms. Think of the one subunit as a computer, with isoforms of desktop, laptop or ipad, 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 (as an enzyme or receptor), and whether it can transport ions or start an intracellular signal. We propose to identify the specific subunits that, when paired together, are an active signal-receptor. We will determine the specific amino acid structure of those subunits. Since both ouabain and progesterone are steroids present in the female at fertilization, we will determine if and how they interact to control Na/K-ATPase actions. We will also determine how other membrane molecules surrounding ATPase affect its function (is your computer in an office or airplane?). This knowledge will help us to protect, predict and improve ATPase function and sperm fertility for domestic and endangered species, and potentially in human reproduction.