Membrane-based signalling pathways controlling sperm capacitation and fertility

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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.