Some assembly required: putting the epithelial sodium channel together.
Some assembly required: putting the epithelial sodium channel together.
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需要一些组装：将上皮钠通道放在一起。
DOI：
10.1074/jbc.r800044200
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Johnson,JohnP
中科院分区：
文献类型：
--
作者：
Butterworth,MichaelB;Weisz,OraA;Johnson,JohnP
上皮钠通道（epithelial sodium channel, ENaC） 2是包括肾、肺、结肠、唾液腺和汗腺在内的上皮细胞顶膜中Na+再吸收的限速步骤(1)。由于ENaC α-亚基的敲除在小鼠中是致命的，因此该通道对于体内平衡是不可或缺的。导致功能获得或丧失的通道异常调节与几种疾病状态的发病机制有关，包括盐敏感性高血压和假性醛固酮减少症II型，也可能导致囊性纤维化肺部疾病的进展（1,2,3）。ENaC是一种高度Na+选择性的酰胺敏感通道，电导相对较低，当存在于细胞膜中时表现为组成性活性(1)。该通道是一种异三聚体蛋白，由三个同源亚基（α， β和γ）组成，化学计量可能为1:1:1（4,5）。δ-亚基可以与α-、β-和γ-ENaC共组装(6)。鉴于其在液体清除和血容量调节中的重要作用，ENaC活性受到严格控制也就不足为奇了。ENaC的顶膜丰度和开放概率会受到多种激素和细胞效应物的影响（1,7）。在翻译和翻译后水平上通道表达的调控是组织特异性的，这些差异在整个通道水平或单个亚基的表达上都是明显的(8)。例如，单个亚基的信息不仅在不同的组织（如肺和肾）中有差异表达，而且在时间上也有差异表达，因此一些亚基的信息是组成性表达，而另一些亚基的信息是激素诱导的(8)。ENaC亚基信息的差异翻译效率也被注意到。在内源性表达的组织和细胞系中，很明显，一些亚基的总细胞和顶膜水平保持不变，而其他亚基则根据改变转运率调节的因素而上调或下调(9)。这种现象被称为ENaC的非协调调节，这个术语首先由Farman及其同事（10,11）应用于肺、肾和结肠中ENaC亚基mRNA的差异类固醇调节。我们之前提出了三种可能的机制来解释这一现象：1)翻译后通道的组装，2)可能存在差异调节的具有替代化学计量的通道，以及3)亚基在某些翻译后位点的拆卸和重组(8)。这些机制并不是相互排斥的，这突出了不止一种途径参与产生被广泛描述为非协调调节的现象的可能性。这篇综述的目的是考虑ENaC在该领域的一些最新发展方面的非协调调节状况，特别是对通道可能的三聚体化学计量学的认识，以及越来越多的证据表明，ENaC亚基池的存在可以参与通道的再循环。最后，我们将讨论在通道蛋白水解激活后，ENaC亚基的不同分子质量形式可能对我们对非配位调节的理解产生的影响。
The epithelial sodium channel (ENaC) 2 constitutes the rate-limiting step in Na+ re-absorption in the apical membrane of epithelia, including kidney, lung, colon, salivary glands, and sweat glands (1). The channel is integral to homeostasis as knock-out of the α-subunit of ENaC is lethal in mice. Abnormal regulation of the channel that results in either gain or loss of function has been implicated in the pathogenesis of several disease states, including forms of salt-sensitive hypertension and pseudohypoaldosteronism type II, and may also contribute to the progression of pulmonary disease in cystic fibrosis (1, 2, 3).ENaC is a highly Na+-selective amiloride-sensitive channel of relatively low conductance that appears to be constitutively active when present in cell membranes (1). The channel is a heterotrimeric protein, made up of three homologous subunits (α, β, and γ) with a likely stoichiometry of 1: 1: 1 (4, 5). A δ-subunit that can co-assemble with α-, β-, and γ-ENaC has also been described (6). Given its essential roles in fluid clearance and regulation of blood volume, it is not surprising that ENaC activity is under strict control. The apical membrane abundance and open probability of ENaC are altered by a wide variety of hormonal and cellular effectors (1, 7). Regulation of channel expression at the translational and post-translational levels is tissue-specific, and these differences are apparent for either whole channel levels or expression of individual subunits (8). For example, message for the individual subunits is differentially expressed not only in distinct tissues such as lung and kidney, but also temporally, so the message for some subunits is expressed constitutively, whereas that for others is induced hormonally (8). Differential translational efficiency of ENaC subunit message has also been noted. In endogenously expressing tissues and cell lines, it is clear that total cellular and apical membrane levels of some subunits remain unchanged, whereas others are either up-or down-regulated in response to factors that alter regulation of transport rate (9). This phenomenon has been referred to as non-coordinate regulation of ENaC, a term first applied by Farman and co-workers (10, 11) to the differential steroid regulation of ENaC subunit mRNA in lung, kidney, and colon. We have previously proposed three possible mechanisms to explain this phenomenon: 1) post-translational assembly of channels, 2) the existence of channels with alternative stoichiometry that may be differentially regulated, and 3) disassembly and recombination of subunits at some post-translational site (8). These mechanisms are not mutually exclusive, which highlights the likelihood that more than one pathway participates in the generation of the phenomenon broadly described as non-coordinate regulation. The purpose of this review is to consider the status of non-coordinate regulation of ENaC with respect to several recent developments in the field, in particular the appreciation of the probable trimeric stoichiometry of the channel and the accumulating evidence that sub-apical pools of ENaC subunits exist that can participate in recycling of the channel. Finally, we will discuss the impact that differing molecular mass forms of the ENaC subunits present at the apical membrane following proteolytic activation of the channel may have on our understanding of non-coordinate regulation.