Calcium Pumps: Why So Many?

Ca2+‐ATPases (pumps) are key to the regulation of Ca2+ in eukaryotic cells: nine are known today, belonging to three multigene families. The three endo(sarco)plasmic reticulum (SERCA) and the four plasma membrane (PMCA) pumps have been known for decades, the two Secretory Pathway Ca2+ ATPase (SPCA) pumps have only become known recently. The number of pump isoforms is further increased by alternative splicing processes. The three pump types share the basic features of the catalytic mechanism, but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca2+. The molecular understanding of the function of all pumps has received great impetus from the solution of the three‐dimensional (3D) structure of one of them, the SERCA pump. This landmark structural advance has been accompanied by the emergence and rapid expansion of the area of pump malfunction. Most of the pump defects described so far are genetic and produce subtler, often tissue and isoform specific, disturbances that affect individual components of the Ca2+‐controlling and/or processing machinery, compellingly indicating a specialized role for each Ca2+ pump type and/or isoform. © 2012 American Physiological Society. Compr Physiol 2:1045‐1060, 2012.