Determinants of K+ vs Na+ Selectivity in Potassium Channels
Determinants of K+ vs Na+ Selectivity in Potassium Channels
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DOI：
10.1021/ja900168k
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发表时间：
2009-06-17
影响因子：
15
通讯作者：
Lim, Carmay
中科院分区：
文献类型：
--
作者：
Dudev, Todor;Lim, Carmay
离子通道是神经系统中不可缺少的组成部分，在调节心脏、骨骼和平滑肌收缩中起着至关重要的作用。钾离子通道控制着许多可兴奋细胞的动作电位，其特点是具有选择K+而不是Na+的显著能力。尽管这种引人注目的离子选择性的分子基础已经通过实验和理论方法进行了广泛的研究，但以下悬而未决的问题仍然存在：(a)与渗透离子结合的水分子数量（即水合值）在多大程度上对K+/Na+竞争很重要？(b)衬孔的配位基团的化学类型和数量对选择性过程是否至关重要？(c)除了提供阳离子连接基团外，通道壁在选择性过程中是否起其他作用？这项工作表明，孔对K+的选择性随着(i)相对于Na+的水化数的增加而增加，（ii） K+偶极子数的增加，（iii） Na+偶极子数的增加，以及（iv）孔提供的配位偶极子数的减少而增加。因此，K+通道中的高K+/Na+选择性可以通过涉及天然离子，金属配位体和蛋白质基质的几个有利因素的组合来实现，即(a)八水合渗透K+， (b)内衬8个羰基配体的孔，(c)精细调整的通道壁物理力学性能，提供有利于渗透K+的高水化数的低介电介质和足够的刚度，以迫使竞争的Na+采用不利的8倍配位。这一点。表明K+通道中最佳的K+/Na+选择性通常并不仅仅来自结构或能量考虑。本文揭示的影响离子选择性的因素有助于解释为什么万霉素和KcsA离子通道具有高度的K+选择性，而NaK通道则是非选择性的。计算结果表明，与钾离子通道中观察到的配位基团数量或化学类型不同的其他孔隙也可能选择K+而不是Na+。
Ion channels, specialized pore-forming proteins, are an indispensable component of the nervous system and play a crucial role in regulating cardiac, skeletal, and smooth muscle contraction. Potassium ion channels, controlling the action potential of a number of excitable cells, are characterized by a remarkable ability to select K+ over Na+. Although the molecular basis for this striking ion selectivity has been a subject of extensive investigations using both experimental and theoretical methods, the following outstanding questions remain: (a) To what extent is the number of water molecules bound to the permeating ion (i.e., the hydration number) important for the K+/Na+ competition? (b) Are the chemical type and number of coordinating groups lining the pore critical for the selectivity process? (c) Apart from providing cation-ligating groups, do the channel walls play any other role in the selectivity process? This work reveals that the pore's selectivity for K+ over Na+ increases with (i) increasing hydration number of K+ relative to that of Na+, (ii) increasing number of K+-coordinating dipoles, (iii) increasing number of Na+-coordinating dipoles, and (iv) decreasing magnitude of the coordinating dipoles provided by the pore. Thus, a high K+/Na+ selectivity in K+ channels could be achieved from a combination of several favorable factors involving the native ion, the metal-coordinating ligands, and the protein matrix, viz., (a) an octahydrated permeating K+, (b) a pore lined with 8 carbonyl ligands, and (c) finely tuned physicomechanical properties of the channel walls providing a low dielectric medium favoring a high hydration number for the permeating K+ and enough stiffness to force the competing Na+ to adopt an unfavorable 8-fold coordination. This. implies that optimal K+/Na+ selectivity in K+ channels generally does not arise from solely structural or energetic consideration. The factors affecting ion selectivity revealed herein help to rationalize why valinomycin and the KcsA ion channels are highly K+-selective, whereas the NaK channel is nonselective. The calculations predict that other pores containing a different number/chemical type of coordinating groups from those observed in potassium channels could also select K+ over Na+.