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{"title":"Epithelial Na <sup>+</sup> Channels Function as Extracellular Sensors.","authors":"Ossama B Kashlan, Xue-Ping Wang, Shaohu Sheng, Thomas R Kleyman","doi":"10.1002/cphy.c230015","DOIUrl":null,"url":null,"abstract":"<p><p>The epithelial Na <sup>+</sup> channel (ENaC) resides on the apical surfaces of specific epithelia in vertebrates and plays a critical role in extracellular fluid homeostasis. Evidence that ENaC senses the external environment emerged well before the molecular identity of the channel was reported three decades ago. This article discusses progress toward elucidating the mechanisms through which specific external factors regulate ENaC function, highlighting insights gained from structural studies of ENaC and related family members. It also reviews our understanding of the role of ENaC regulation by the extracellular environment in physiology and disease. After familiarizing the reader with the channel's physiological roles and structure, we describe the central role protein allostery plays in ENaC's sensitivity to the external environment. We then discuss each of the extracellular factors that directly regulate the channel: proteases, cations and anions, shear stress, and other regulators specific to particular extracellular compartments. For each regulator, we discuss the initial observations that led to discovery, studies investigating molecular mechanism, and the physiological and pathophysiological implications of regulation. © 2024 American Physiological Society. Compr Physiol 14:5407-5447, 2024.</p>","PeriodicalId":10573,"journal":{"name":"Comprehensive Physiology","volume":null,"pages":null},"PeriodicalIF":4.2000,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11309579/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Comprehensive Physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1002/cphy.c230015","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
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Abstract
The epithelial Na + channel (ENaC) resides on the apical surfaces of specific epithelia in vertebrates and plays a critical role in extracellular fluid homeostasis. Evidence that ENaC senses the external environment emerged well before the molecular identity of the channel was reported three decades ago. This article discusses progress toward elucidating the mechanisms through which specific external factors regulate ENaC function, highlighting insights gained from structural studies of ENaC and related family members. It also reviews our understanding of the role of ENaC regulation by the extracellular environment in physiology and disease. After familiarizing the reader with the channel's physiological roles and structure, we describe the central role protein allostery plays in ENaC's sensitivity to the external environment. We then discuss each of the extracellular factors that directly regulate the channel: proteases, cations and anions, shear stress, and other regulators specific to particular extracellular compartments. For each regulator, we discuss the initial observations that led to discovery, studies investigating molecular mechanism, and the physiological and pathophysiological implications of regulation. © 2024 American Physiological Society. Compr Physiol 14:5407-5447, 2024.
上皮细胞 Na + 通道作为细胞外传感器发挥作用
上皮 Na + 通道(ENaC)位于脊椎动物特定上皮的顶端表面,在细胞外液平衡中发挥着关键作用。早在三十年前报告ENaC通道的分子特征之前,就有证据表明ENaC能感知外部环境。本文讨论了在阐明特定外部因素调控 ENaC 功能的机制方面取得的进展,重点介绍了从 ENaC 及相关家族成员的结构研究中获得的见解。文章还回顾了我们对ENaC受细胞外环境调控在生理学和疾病中的作用的理解。在让读者熟悉通道的生理作用和结构之后,我们介绍了蛋白质异构在 ENaC 对外部环境的敏感性中所起的核心作用。然后,我们将逐一讨论直接调控通道的细胞外因素:蛋白酶、阳离子和阴离子、剪切应力以及特定细胞外区室的其他调控因子。对于每种调节因子,我们都会讨论导致发现的最初观察结果、分子机制研究以及调节对生理和病理生理学的影响。© 2024 美国生理学会。Compr Physiol 14:5407-5447, 2024.
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