Abstract
Calcium ions (Ca(2+)) are prominent cell signaling effectors that regulate a wide variety of cellular processes. Among the different players in Ca(2+) homeostasis, primary active Ca(2+) transporters are responsible for keeping low basal Ca(2+) levels in the cytosol while establishing steep Ca(2+) gradients across intracellular membranes or the plasma membrane. This review summarizes our current knowledge on the three types of primary active Ca(2+)-ATPases: the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) pumps, the secretory pathway Ca(2+)- ATPase (SPCA) isoforms, and the plasma membrane Ca(2+)-ATPase (PMCA) Ca(2+)-transporters. We first discuss the Ca(2+) transport mechanism of SERCA1a, which serves as a reference to describe the Ca(2+) transport of other Ca(2+) pumps. We further highlight the common and unique features of each isoform and review their structure-function relationship, expression pattern, regulatory mechanisms, and specific physiological roles. Finally, we discuss the increasing genetic and in vivo evidence that links the dysfunction of specific Ca(2+)-ATPase isoforms to a broad range of human pathologies, and highlight emerging therapeutic strategies that target Ca(2+) pumps.