Current and Future Landscape of SERCAs' Functions in Non-Excitatory Cells and Diseases

Calcium (Ca²⁺) signaling as the primary intracellular second messenger orchestrates a myriad of physiological processes. Maintaining Ca²⁺ homeostasis relies on Ca²⁺ channels, pumps, exchangers, and buffers. Sarco/endoplasmic reticulum Ca²⁺-ATPases (SERCAs or ATP2A) encoded by ATP2A1, ATP2A2, or ATP2A3 are primary Ca²⁺ pumps localized on the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) that actively sequester Ca²⁺ from the cytoplasm back to the ER/SR, thereby preventing the detrimental overload of cytoplasmic Ca²⁺ concentration. Recent studies have highlighted the significant roles and the underlying mechanisms of SERCAs in non-excitatory cells such as those within epithelial, adipose, immune, and reproductive systems or tissues. This article aims to provide a comprehensive summary of the functional characteristics and regulatory mechanisms of the SERCA family, with a particular focus on the latest research concerning their roles and mechanisms in various non-excitatory cells and related cancers. This work will provide insight into understanding the Ca²⁺ signaling regulatory networks mediated by SERCAs and their implications for the diagnosis and treatment of Ca²⁺ dyshomeostasis-related diseases and propose potentially constructive suggestions for the direction of research around Ca²⁺ signaling transductions, as well as guiding strategies for disease diagnosis, treatment, and drug development by targeting SERCAs.