质膜Ca²⁺- ATP酶超快转运的分子机制，这一成果由马克斯·普朗克分子生理学研究所Stefan Raunsern研究团队经过不懈努力而取得。相关论文于2025年8月20日发表在《自然》杂志上。

在这里，该团队介绍了小鼠PMCA2在其转运周期的八个不同阶段中存在和不存在其附属亚基神经活素的结构。结合完整细胞中精确跟踪PMCA介导的Ca²⁺外移离子的全细胞记录，这些结构使他们能够建立PMCA的第一个综合运输模型，揭示疾病导管突变的作用，并揭示调节性PMCA-磷脂相互作用的结构基础。PtdIns(4,5)P₂的转运周期依赖动力学是其作为促进Ca²⁺快速释放和打开反离子通道的“锁存器”作用的基础。这些行动是维持超高速运输周期所必需的。

此外，该课题组研究人员发现PtdIns(4,5) p₂结合位点是药物介导的细胞内Ca²⁺水平调控的一个意想不到的靶点。他们的工作为原生PMCA型Ca²⁺泵的独特快速运行及其由膜脂和药物控制提供了详细的结构见解。

据了解，严格控制细胞内Ca²⁺水平是基本的，因为它们被主题控制许多信号转导途径。质膜Ca²⁺-ATP酶（PMCAs）在这一过程中起着至关重要的作用，它通过从细胞质溶胶向细胞外空间的陡峭浓度梯度挤压Ca²⁺。尽管PMCA生物学的新细节不断被发现，但这些泵最显著特征的结构基础，即千赫兹范围内的运输速率和质膜磷脂PtdIns(4,5)P₂对活性的调节，到目前为止仍然是未知的。

附：英文原文

Title: Molecular mechanism of ultrafast transport by plasma membrane Ca2+-ATPases

Author: Vinayagam, Deivanayagabarathy, Sitsel, Oleg, Schulte, Uwe, Constantin, Cristina E., Oosterheert, Wout, Prumbaum, Daniel, Zolles, Gerd, Fakler, Bernd, Raunser, Stefan

Issue&Volume: 2025-08-20

Abstract: Tight control of intracellular Ca2+ levels is fundamental as they are used to control numerous signal transduction pathways1. Plasma membrane Ca2+-ATPases (PMCAs) have a crucial role in this process by extruding Ca2+ against a steep concentration gradient from the cytosol to the extracellular space2. Although new details of PMCA biology are constantly being uncovered, the structural basis of the most distinguishing features of these pumps, namely, transport rates in the kilohertz range and regulation of activity by the plasma membrane phospholipid PtdIns(4,5)P2, has so far remained elusive. Here we present the structures of mouse PMCA2 in the presence and absence of its accessory subunit neuroplastin in eight different stages of its transport cycle. Combined with whole-cell recordings that accurately track PMCA-mediated Ca2+ extrusion in intact cells, these structures enable us to establish the first comprehensive transport model for a PMCA, reveal the role of disease-causing mutations and uncover the structural underpinnings of regulatory PMCA–phospholipid interaction. The transport cycle-dependent dynamics of PtdIns(4,5)P2 are fundamental for its role as a ‘latch’ promoting the fast release of Ca2+ and opening a passageway for counter-ions. These actions are required for maintaining the ultra-fast transport cycle. Moreover, we identify the PtdIns(4,5)P2-binding site as an unanticipated target for drug-mediated manipulation of intracellular Ca2+ levels. Our work provides detailed structural insights into the uniquely fast operation of native PMCA-type Ca2+ pumps and its control by membrane lipids and drugs.

DOI: 10.1038/s41586-025-09402-3

Source: https://www.nature.com/articles/s41586-025-09402-3