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Tunable pK_a values and the basis of opposite charge selectivities in nicotinic-type receptors

机译：烟碱型受体的可调pK_a值和相反电荷选择性的基础

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摘要

Among ion channels, only the nicotinic-receptor superfamily has evolved to generate both cation- and anion-selective members. Although other, structurally unrelated, neurotransmitter-gated cation channels exist, no other type of neurotransmitter-gated anion channel, and thus no other source of fast synaptic inhibitory signals, has been described so far. In addition to the seemingly straightforward electrostatic effect of the presence (in the cation-selective members) or absence (in the anion-selective ones) of a ring of pore-facing carboxylates, mutational studies have identified other features of the amino-acid sequence near the intracel-lular end of the pore-lining transmembrane segments (M2) that are also required to achieve the high charge selectivity shown by native channels~(1-10). However, the mechanism underlying this more subtle effect has remained elusive~(11) and a subject of speculation. Here we show, using single-channel electrophysiological recordings to estimate the protonation state of native ionizable side chains, that anion-selective-type sequences favour whereas cation-selective-type sequences prevent the protonation of the conserved, buried basic residues at the intracellular entrance of the pore (the M2 0' position). We conclude that the previously unrecognized tunable charge state of the 0' ring of buried basic side chains is an essential feature of these channels' versatile charge-selectivity filter.
机译：在离子通道中，只有烟碱受体超家族已经进化为生成阳离子和阴离子选择性成员。尽管存在其他在结构上不相关的神经递质门控阳离子通道，但到目前为止，没有其他类型的神经递质门控阴离子通道，因此没有其他快速突触抑制信号的来源。除了存在（在阳离子选择性成员中）或不存在（在阴离子选择性成员中）的面对孔的羧酸盐环的看似直接的静电效应，突变研究还确定了氨基酸序列的其他特征孔壁跨膜片段（M2）的胞内端附近也需要达到天然通道〜（1-10）所示的高电荷选择性。然而，这种更微妙的影响的机制仍然难以捉摸（11），也是一个推测的话题。在这里，我们表明，使用单通道电生理记录来估计天然可电离侧链的质子化状态，表明阴离子选择型序列有利于阳离子选择型序列，而防止了细胞内入口处保守的掩埋碱性残基的质子化孔的位置（M2 0'位置）。我们得出的结论是，掩埋的基本侧链的0'环以前无法识别的可调电荷状态是这些通道的通用电荷选择性滤波器的基本特征。

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  • 来源
    《Nature》 |2011年第7352期|p.526-530|共5页
  • 作者

    Gisela D. Cymes; Claudio Grosman;

  • 作者单位

    Department of Molecular and Integrative Physiology, Center for Biophysics and Computational Biology, and Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801,USA;

    Department of Molecular and Integrative Physiology, Center for Biophysics and Computational Biology, and Neuroscience Program, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801,USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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