The plasma membrane calcium pump: Functional domains, regulation of the activity, and tissue specificity of isoform expression

The plasma membrane Ca2+ pump is responsible for the fine regulation of the intracellular Ca2+ level and is thus involved in the control of several cellular processes. The activity of the pump is regulated by a multiplicity of mechanisms, among which are calmodulin, acidic phospholipids, kinase-mediated phosphorylation, or an oligomerization process. The C-terminal part of the molecule interacts with the region of the pump close to the active site, leading to the decrease of the activity in the resting state. Four genes coding for different isoforms of the plasma membrane Ca2+ ATPase are known in humans. Isoform 1 and 4 represent housekeeping isoforms, whereas isoforms 2 and 3 are only present in specialized tissues. The variability of the protein is further increased by alternative RNA splicing at two sites (A, C). Alternative splicing occurs within (splice site C) or near (splice site A) regions coding for regulatory domains of the protein. In all isoforms a corresponding splice form exists at both splice sites. These common splice forms are present in all tissues, whereas isoform unique splice forms are normally only present in specialized tissues. In neuronal tissues all isoforms and almost the complete set of splice forms are found. The transcripts of the different isoforms are distributed in a region-specific manner in neuronal tissues.