Primary Active Ca²⁺ Transport Systems in Health and Disease

Calcium ions (Ca²⁺) are prominent cell signaling effectors that regulate a wide variety of cellular processes. Among the different players in Ca²⁺ homeostasis, primary active Ca²⁺ transporters are responsible for keeping low basal Ca²⁺ levels in the cytosol while establishing steep Ca²⁺ gradients across intracellular membranes or the plasma membrane. This review summarizes our current knowledge on the three types of primary active Ca²⁺-ATPases: the sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA) pumps, the secretory pathway Ca²⁺- ATPase (SPCA) isoforms, and the plasma membrane Ca²⁺-ATPase (PMCA) Ca²⁺-transporters. We first discuss the Ca²⁺ transport mechanism of SERCA1a, which serves as a reference to describe the Ca²⁺ transport of other Ca²⁺ 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 Ca²⁺-ATPase isoforms to a broad range of human pathologies, and highlight emerging therapeutic strategies that target Ca²⁺ pumps.