Sperm phenotype of mice carrying a gene deletion for the plasma membrane calcium/calmodulin dependent ATPase 4.

The sarcolemmal calcium pumps (PMCA for plasma membrane calcium/calmodulin dependent ATPase) are a family of 10 transmembrane domain proteins ejecting calcium from the cytosol. They are encoded by four independent genes and at least 21 splice variants have been described. Isoforms 1 and 4 are ubiquitous, whereas isoforms 2 and 3 are confined to neurons and few other cells (e.g. isoform 2 in the myocardium). In non-excitable cells they are thought to be the only calcium ejection systems and their function as governors of calcium balance is hence intuitive since cells cannot survive in a state of calcium overload. Differences in the affinity of the various isoforms for calcium, ATP and calmodulin have been described, but it is unclear whether the pumps have specialized functions over and above their 'housekeeping' role. In particular, in excitable cells, most calcium is ejected by the sodium/calcium exchanger suggesting that the PMCAs may have evolved into a specialized role. Recently, our group has identified a number of specialized functions of the PMCAs, notably a prominent regulatory role of PMCA4 (splice variant b) for neuronal NO synthase as well as for the Ras pathway. In addition, mice carrying a genetic deletion of the PMCA4 gene showed normal female, but completely infertile male animals. This is due to a highly specific defect in sperm motility, which is reduced to zero, with normal fertilization capacity. Overall, a scenario emerges where the plasma membrane calcium pumps fulfil roles far beyond the traditional housekeeping function, notably in cell signaling, sperm motility, and potentially in cell division. Consequently, we are currently exploring their potential as future drug targets for a variety of conditions, as well as their potential use in the development of a male contraception.