Plasma Membrane Calcium ATPases as Novel Candidates for Therapeutic Agent Development
Plasma Membrane Calcium ATPases as Novel Candidates for Therapeutic Agent Development
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DOI：
10.18433/j3z011
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发表时间：
2013-01-01
影响因子：
2.7
通讯作者：
Strehler, Emanuel E.
中科院分区：
文献类型：
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作者：
Strehler, Emanuel E.
质膜Ca ~（2+）ATP酶（Plasma membrane Ca ~（2+）ATPases，PMCAs）是一种高度调控的真核细胞Ca ~（2+）外排转运蛋白。不同的PMCA异构体涉及各种任务的Ca 2+调节，包括大量的Ca 2+运输和本地化的Ca 2+信号在特定的膜微区。越来越多的证据表明，不同PMCAs的丢失、突变或不适当表达与高血压、低骨密度和男性不育到听力损失和小脑共济失调等病理学相关。与Ca 2+内流通道相比，PMCAs作为药物开发的靶点远远落后，主要是由于缺乏对其结构和特定功能的详细了解。这是迅速改变由于综合努力相结合的生物化学，结构，细胞和生理学研究表明，选择性调节PMCA亚型可能是不同的和复杂的疾病的管理中的治疗价值。结构上知情的合理设计和高通量小分子文库筛选是有前途的策略，预计将导致特定的和异构体选择性的PMCA功能调节剂。这篇简短的评论将提供一个概述的不同的作用所发挥的PMCA亚型在不同的细胞和组织和他们的新兴参与病理生理过程中，总结最近的进展，在获得结构信息的PMCA，并讨论当前和未来的战略，以开发特定的PMCA抑制剂和激活剂的潜在的治疗应用。
Plasma membrane Ca2+ ATPases (PMCAs) are highly regulated transporters responsible for Ca2+ extrusion from all eukaryotic cells. Different PMCA isoforms are implicated in various tasks of Ca2+ regulation including bulk Ca2+ transport and localized Ca2+ signaling in specific membrane microdomains. Accumulating evidence shows that loss, mutation or inappropriate expression of different PMCAs is associated with pathologies ranging from hypertension, low bone density and male infertility to hearing loss and cerebellar ataxia. Compared to Ca2+ influx channels, PMCAs have lagged far behind as targets for drug development, mainly due to the lack of detailed understanding of their structure and specific function. This is rapidly changing thanks to integrated efforts combining biochemical, structural, cellular and physiological studies suggesting that selective modulation of PMCA isoforms may be of therapeutic value in the management of different and complex diseases. Both structurally informed rational design and high-throughput small molecule library screenings are promising strategies that are expected to lead to specific and isoform-selective modulators of PMCA function. This short review will provide an overview of the diverse roles played by PMCA isoforms in different cells and tissues and their emerging involvement in pathophysiological processes, summarize recent progress in obtaining structural information on the PMCAs, and discuss current and future strategies to develop specific PMCA inhibitors and activators for potential therapeutic applications.