Primary Active Ca²⁺ Transport Systems in Health and Disease

Abstract

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.