PIEZO1 通道的药理学。

IF 6.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Jacob A. Kinsella, Marjolaine Debant, Gregory Parsonage, Lara C. Morley, Muath Bajarwan, Charlotte Revill, Richard Foster, David J. Beech
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引用次数: 0

摘要

PIEZO1 是一种真核生物膜蛋白,它以三聚体的形式组装成具有钙渗透性的非选择性阳离子通道,在包括血细胞、内皮细胞、上皮细胞、成纤维细胞和干细胞在内的各种细胞类型以及包括骨骼、淋巴管和肌肉在内的各种系统中具有精湛的机械力感应和力传导能力。该通道具有广泛的作用,被认为是癌症、心血管、牙科、胃肠道、肝胆、感染、肌肉骨骼、神经系统、眼科、妊娠、肾脏、呼吸和泌尿系统疾病等各种疾病的新型疗法的靶点。PIEZO1 调制剂的鉴定工作尚处于起步阶段,但已经出现了一些有用的实验工具来激活或抑制该通道。目前已知的 Yoda 系列小分子激动剂具有基本的结构-活性关系,这些激动剂显示出多种物理化学和药理特性的潜力。Yoda1 令人感兴趣的作用包括刺激清除多余的脑脊液。尽管 PIEZO1 的表达范围很广,但仍有机会对其进行选择性的正向或负向调节,而不会产生难以忍受的不良反应。在此,我们对这一药理学的进展进行了集中、非系统的叙述性回顾,并讨论了该领域未来潜在的研究方向。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pharmacology of PIEZO1 channels

Pharmacology of PIEZO1 channels

PIEZO1 is a eukaryotic membrane protein that assembles as trimers to form calcium-permeable, non-selective cation channels with exquisite capabilities for mechanical force sensing and transduction of force into effect in diverse cell types that include blood cells, endothelial cells, epithelial cells, fibroblasts and stem cells and diverse systems that include bone, lymphatics and muscle. The channel has wide-ranging roles and is considered as a target for novel therapeutics in ailments spanning cancers and cardiovascular, dental, gastrointestinal, hepatobiliary, infectious, musculoskeletal, nervous system, ocular, pregnancy, renal, respiratory and urological disorders. The identification of PIEZO1 modulators is in its infancy but useful experimental tools emerged for activating, and to a lesser extent inhibiting, the channels. Elementary structure–activity relationships are known for the Yoda series of small molecule agonists, which show the potential for diverse physicochemical and pharmacological properties. Intriguing effects of Yoda1 include the stimulated removal of excess cerebrospinal fluid. Despite PIEZO1's broad expression, opportunities are suggested for selective positive or negative modulation without intolerable adverse effects. Here we provide a focused, non-systematic, narrative review of progress with this pharmacology and discuss potential future directions for research in the area.

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来源期刊
CiteScore
15.40
自引率
12.30%
发文量
270
审稿时长
2.0 months
期刊介绍: The British Journal of Pharmacology (BJP) is a biomedical science journal offering comprehensive international coverage of experimental and translational pharmacology. It publishes original research, authoritative reviews, mini reviews, systematic reviews, meta-analyses, databases, letters to the Editor, and commentaries. Review articles, databases, systematic reviews, and meta-analyses are typically commissioned, but unsolicited contributions are also considered, either as standalone papers or part of themed issues. In addition to basic science research, BJP features translational pharmacology research, including proof-of-concept and early mechanistic studies in humans. While it generally does not publish first-in-man phase I studies or phase IIb, III, or IV studies, exceptions may be made under certain circumstances, particularly if results are combined with preclinical studies.
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