A mutation in the extracellular domain of the α7 nAChR reduces calcium permeability.
A mutation in the extracellular domain of the α7 nAChR reduces calcium permeability.
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DOI：
10.1007/s00424-013-1385-y
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发表时间：
2014-08
影响因子：
4.5
通讯作者：
Yakel, Jerrel L.
中科院分区：
文献类型：
--
作者：
Colon-Saez, Jose O.;Yakel, Jerrel L.
α7神经元烟碱乙酰胆碱受体（nAChR）在哺乳动物脑中表达的不同nAChR亚型中显示出最高的钙渗透性，并且可以影响细胞事件，包括神经递质释放、第二信使级联、细胞存活和凋亡。nAChR中阳离子的选择性被认为部分是通过位于通道口两侧并增加相对阳离子浓度的阴离子残基实现的。突变研究提高了我们对第二跨膜结构域和通道的胞内环在离子选择性中的作用的理解。然而，很少有人知道的影响，细胞外结构域（ECD）在离子渗透。在α7 nAChR中，已发现ECD含有一个10个谷氨酸酯（每个亚基2个）的环，据信该环面向孔腔，可吸引阳离子进行渗透。使用诱变以及电生理学和成像技术的组合，我们测试了这些天冬氨酸残基在大鼠α7 nAChR的钙渗透性中的可能参与。我们发现，这些残基之一（44位的天冬氨酸）似乎是必不可少的，因为将其突变为丙氨酸导致全细胞和单通道反应的幅度降低，并且在大多数细胞中可检测到的钙变化完全消失，这表明α7 nAChR的ECD在钙渗透中起关键作用。
The α7 neuronal nicotinic acetylcholine receptor (nAChR) displays the highest calcium permeability among the different subtypes of nAChRs expressed in the mammalian brain and can impact cellular events including neurotransmitter release, second messenger cascades, cell survival, and apoptosis. The selectivity for cations in nAChRs is thought to be achieved in part by anionic residues which are located on either side of the channel mouth and increase relative cationic concentration. Mutagenesis studies have improved our understanding of the role of the second transmembrane domain and the intracellular loop of the channel in ion selectivity. However, little is known about the influence that the extracellular domain (ECD) plays in ion permeation. In the α7 nAChR, it has been found that the ECD contains a ring of ten aspartates (two per subunit) that is believed to face the lumen of the pore and could attract cations for permeation. Using mutagenesis and a combination of electrophysiology and imaging techniques, we tested the possible involvement of these aspartate residues in the calcium permeability of the rat α7 nAChR. We found that one of these residues (the aspartate at position 44) appears to be essential since mutating it to alanine resulted in a decrease in amplitude for both whole cell and single-channel responses and in the complete disappearance of detectable calcium changes in most cells, which indicates that the ECD of the α7 nAChR plays a key role in calcium permeation.
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影响因子：
16.2
作者：
Gu Z;Yakel JL
通讯作者：
Yakel JL
影响因子：
5.5
作者：
Fucile, Sergio;Sucapane, Antonietta;Engel, Andrew G.
通讯作者：
Engel, Andrew G.
影响因子：
5.6
作者：
Pohanka M
通讯作者：
Pohanka M
影响因子：
4.8
作者：
Livesey, Matthew R.;Cooper, Michelle A.;Peters, John A.
通讯作者：
Peters, John A.
影响因子：
25
作者：
Li SX;Huang S;Bren N;Noridomi K;Dellisanti CD;Sine SM;Chen L
通讯作者：
Chen L