Yu Jingyan, Wang Hongyu, Ding Mengqian, Zhao Xiuling, Zhang Xiaoning
Institute of Reproductive Medicine, Medical School, Nantong University, Nantong, P. R. China.
Bioessays. 2025 Aug;47(8):e70029. doi: 10.1002/bies.70029. Epub 2025 Jun 6.
Calcium (Ca) signaling as the primary intracellular second messenger orchestrates a myriad of physiological processes. Maintaining Ca homeostasis relies on Ca channels, pumps, exchangers, and buffers. Sarco/endoplasmic reticulum Ca-ATPases (SERCAs or ATP2A) encoded by ATP2A1, ATP2A2, or ATP2A3 are primary Ca pumps localized on the endoplasmic reticulum (ER)/sarcoplasmic reticulum (SR) that actively sequester Ca from the cytoplasm back to the ER/SR, thereby preventing the detrimental overload of cytoplasmic Ca 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 Ca signaling regulatory networks mediated by SERCAs and their implications for the diagnosis and treatment of Ca dyshomeostasis-related diseases and propose potentially constructive suggestions for the direction of research around Ca signaling transductions, as well as guiding strategies for disease diagnosis, treatment, and drug development by targeting SERCAs.
钙（Ca）信号作为主要的细胞内第二信使，协调着无数的生理过程。维持钙稳态依赖于钙通道、泵、交换体和缓冲剂。由ATP2A1、ATP2A2或ATP2A3编码的肌浆网/内质网钙ATP酶（SERCAs或ATP2A）是定位在内质网（ER）/肌浆网（SR）上的主要钙泵，它们将钙从细胞质中主动隔离回ER/SR，从而防止细胞质钙浓度的有害过载。最近的研究突出了SERCAs在非兴奋性细胞（如上皮、脂肪、免疫和生殖系统或组织中的细胞）中的重要作用及潜在机制。本文旨在全面总结SERCAs家族的功能特性和调控机制，特别关注其在各种非兴奋性细胞及相关癌症中的作用和机制的最新研究。这项工作将有助于深入理解由SERCAs介导的钙信号调控网络及其对钙稳态失调相关疾病诊断和治疗的意义，并为围绕钙信号转导的研究方向提出潜在的建设性建议，以及指导针对SERCAs的疾病诊断、治疗和药物开发策略。
