Plasma membrane Ca2+-ATPase: from a housekeeping function to a versatile signaling role

Plasma membrane Ca2+-ATPases (PMCAs) are high-affinity calcium pumps that contribute to the maintenance of intracellular Ca2+ homeostasis by exporting Ca2+ from the cytosol to the extracellular environment. Mammals have four genes encoding the proteins PMCA1 through PMCA4. Each gene transcript is alternatively spliced to generate several variants. Their distribution is tissue- and cell-specific and undergoes regulation during cell development and differentiation. Traditionally, these pumps have been considered to play a housekeeping role in controlling basal Ca2+ levels, but more recently, it became clear that the presence (and the co-expression) of different isoforms must be related to a more specialized function. Only one of the four genes (encoding PMCA2) has been causally linked to disease in mammals: Several spontaneous mutations are responsible for deafness and ataxia. Other complex human disease phenotype like hearing loss, cardiac function, and infertility are likely to be associated with PMCA function, but no spontaneous mutations in other PMCA genes than PMCA2 are so far identified. The evidence of their involvement in disease phenotypes comes from studies on isoform-specific knockout mice. In this review, I will discuss briefly the general role of PMCA as essential component of Ca2+ homeostasis machinery and focus on its emerging role as signaling molecule with particular attention on the diseases caused by PMCA dysfunction.