Functional features of the "finger" domain of the DEG/ENaC channels MEC-4 and UNC-8.
Functional features of the "finger" domain of the DEG/ENaC channels MEC-4 and UNC-8.
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DEG/ENaC 通道 MEC-4 和 UNC-8 的“手指”域的功能特征。
DOI：
10.1152/ajpcell.00297.2017
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Bianchi,Laura
中科院分区：
文献类型：
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作者：
Matthewman,Cristina;Johnson,ChristinaK;Miller3rd,DavidM;Bianchi,Laura
MEC-8和MEC-4是电压非依赖性Na+通道的退变蛋白/上皮Na+通道（DEG/ENaC）家族的两个成员，它们具有高度的序列同源性和功能相似性。例如，两者都可以被基因突变过度激活[E3 -8（d）和MEC-4（d）]，这些基因突变通过坏死诱导神经元死亡。两者在体内都依赖于伴侣蛋白MEC-6的功能，如由过度活跃的β-8和MEC-4通道诱导的神经元死亡被MEC-6中的无效突变阻止的发现所证明的。MEC-8和MEC-4在三个主要方面功能不同：1）MEC-4是钙可渗透的，而MEC-8不是;2）MEC-8，而不是MEC-4，被细胞外钙和镁在微摩尔范围内阻断;和3）MEC-6增加卵母细胞表面的MEC-4通道的数量，但对MEC-8没有这种影响。我们先前报道MEC-4的Ca 2+渗透性由第二跨膜结构域赋予。我们在这里表明，细胞外的“手指”结构域的β-8是足以介导抑制二价阳离子和MEC-6的调节也取决于这个区域。因此，我们的工作证实，手指结构域的房屋残基参与门控这类通道，并首次表明，手指结构域也介导的伴侣蛋白MEC-6的调节。考虑到指状结构域是DEG/ENaC家族中最具分歧的区域，我们推测它以独特的方式影响通道运输和功能，这取决于通道亚基。
UNC-8 and MEC-4 are two members of the degenerin/epithelial Na+channel (DEG/ENaC) family of voltage-independent Na+channels that share a high degree of sequence homology and functional similarity. For example, both can be hyperactivated by genetic mutations [UNC-8(d) and MEC-4(d)] that induce neuronal death by necrosis. Both depend in vivo on chaperone protein MEC-6 for function, as demonstrated by the finding that neuronal death induced by hyperactive UNC-8 and MEC-4 channels is prevented by null mutations inmec-6. UNC-8 and MEC-4 differ functionally in three major ways:1) MEC-4 is calcium permeable, whereas UNC-8 is not;2) UNC-8, but not MEC-4, is blocked by extracellular calcium and magnesium in the micromolar range; and3) MEC-6 increases the number of MEC-4 channels at the cell surface in oocytes but does not have this effect on UNC-8. We previously reported that Ca2+permeability of MEC-4 is conferred by the second transmembrane domain. We show here that the extracellular “finger” domain of UNC-8 is sufficient to mediate inhibition by divalent cations and that regulation by MEC-6 also depends on this region. Thus, our work confirms that the finger domain houses residues involved in gating of this channel class and shows for the first time that the finger domain also mediates regulation by chaperone protein MEC-6. Given that the finger domain is the most divergent region across the DEG/ENaC family, we speculate that it influences channel trafficking and function in a unique manner depending on the channel subunit.