Plasma membrane Ca²⁺ ATPases as dynamic regulators of cellular calcium handling

Plasma membrane Ca²⁺ ATPases (PMCAs) are essential components of the cellular toolkit to regulate and fine-tune cytosolic Ca²⁺ concentrations. Historically, the PMCAs have been assigned a housekeeping role in the maintenance of intracellular Ca²⁺ homeostasis. More recent work has revealed a perplexing multitude of PMCA isoforms and alternative splice variants, raising questions about their specific role in Ca²⁺ handling under conditions of varying Ca²⁺ loads. Studies on the kinetics of individual isoforms, combined with expression and localization studies suggest that PMCAs are optimized to function in Ca²⁺ regulation according to tissue- and cell-specific demands. Different PMCA isoforms help control slow, tonic Ca²⁺ signals in some cells and rapid, efficient Ca²⁺ extrusion in others. Localized Ca²⁺ handling requires targeting of the pumps to specialized cellular locales, such as the apical membrane of cochlear hair cells or the basolateral membrane of kidney epithelial cells. Recent studies suggest that alternatively spliced regions in the PMCAs are responsible for their unique targeting, membrane localization, and signaling cross-talk. The regulated deployment and retrieval of PMCAs from specific membranes provide a dynamic system for a cell to respond to changing needs of Ca²⁺ regulation.