Plasma membrane calcium ATPases: From generic Ca²⁺ sump pumps to versatile systems for fine-tuning cellular Ca²⁺

The plasma membrane calcium ATPases (PMCAs) are ATP-driven primary ion pumps found in all eukaryotic cells. They are the major high-affinity calcium extrusion system for expulsion of Ca²⁺ ions from the cytosol and help restore the low resting levels of intracellular [Ca²⁺] following the temporary elevation of Ca²⁺ generated during Ca²⁺ signaling. Due to their essential role in the maintenance of cellular Ca²⁺ homeostasis they were initially thought to be "sump pumps" for Ca²⁺ removal needed by all cells to avoid eventual calcium overload. The discovery of multiple PMCA isoforms and alternatively spliced variants cast doubt on this simplistic assumption, and revealed instead that PMCAs are integral components of highly regulated multi-protein complexes fulfilling specific roles in calcium-dependent signaling originating at the plasma membrane. Biochemical, genetic, and physiological studies in gene-manipulated and mutant animals demonstrate the important role played by specific PMCAs in distinct diseases including those affecting the peripheral and central nervous system, cardiovascular disease, and osteoporosis. Human PMCA gene mutations and allelic variants associated with specific disorders continue to be discovered and underline the crucial role of different PMCAs in particular cells, tissues and organs.