Ion permeation and glutamate residues linked by Poisson-Nernst-Planck theory in L-type calcium channels
Ion permeation and glutamate residues linked by Poisson-Nernst-Planck theory in L-type calcium channels
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DOI：
10.1016/s0006-3495(98)74048-2
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发表时间：
1998-09-01
影响因子：
3.4
通讯作者：
Eisenberg, B
中科院分区：
文献类型：
--
作者：
Nonner, W;Eisenberg, B
L型钙通道含有一簇四个带电谷氨酸残基（EEEE位点），这似乎是高钙特异性所必需的。为了理解这种高度带电的结构如何产生在该通道中观察到的电流和选择性，需要将电荷与电流联系起来的理论。我们使用一个扩展的泊松-能斯特-普朗克（PNP 2）理论计算（平均）库仑相互作用，从而检查的平均场静电相互作用中产生的电流和选择性的作用。孔被建模为具有锥形心房的中心圆柱体;圆柱体（即，“孔隙本身”）含有与1 - 4个羧基相等的固定电荷的均匀体积密度。孔适当的分配离子特定的，但空间均匀，扩散系数和过剩的化学势。因此，静电选择价计算自洽，选择其他功能也是允许的。四种离子种类（Na，Ca，Cl和H）的系统所需的五个外部参数从三个极限电导和两个临界离子浓度的已发表的测量值分析确定，同时将孔作为宏观离子交换系统与均匀的浴溶液平衡。用这些参数求解扩展PNP方程，并将预测结果与跨膜电压范围内各种溶液中测得的电流进行比较。扩展的PNP理论准确地预测了电流-电压关系、所观察到的电流中的异常摩尔分数效应、不同Ca和Na浓度的饱和效应以及质子的阻挡。孔的几何形状，介电常数，和羧基的数量只有微弱的影响。本文中钙通量的成功预测表明，特设的静电参数，多个离散的结合位点，和单文件移动的逻辑假设都是不必要的预测渗透在Ca通道在很宽的范围内的条件。然而，还需要进一步的工作来理解固定电荷的原子起源、过量化学势和通道的扩散系数。附录使用PNP 2理论来预测离子电流的已发表的“势垒和阱”的能量分布的这个通道。
L-type Ca channels contain a cluster of four charged glutamate residues (EEEE locus), which seem essential for high Ca specificity. To understand how this highly charged structure might produce the currents and selectivity observed in this channel, a theory is needed that relates charge to current. We use an extended Poisson-Nernst-Planck (PNP2) theory to compute (mean) Coulombic interactions and thus to examine the role of the mean field electrostatic interactions in producing current and selectivity. The pore was modeled as a central cylinder with tapered atria; the cylinder (i.e., "pore proper") contained a uniform volume density of fixed charge equivalent to that of one to four carboxyl groups. The pore proper was assigned ion-specific, but spatially uniform, diffusion coefficients and excess chemical potentials. Thus electrostatic selection by valency was computed self-consistently, and selection by other features was also allowed. The five external parameters needed for a system of four ionic species (Na, Ca, CI, and H) were determined analytically from published measurements of three limiting conductances and two critical ion concentrations, while treating the pore as a macroscopic ion-exchange system in equilibrium with a uniform bath solution. The extended PNP equations were solved with these parameters, and the predictions were compared to currents measured in a variety of solutions over a range of transmembrane voltages. The extended PNP theory accurately predicted current-voltage relations, anomalous mole fraction effects in the observed current, saturation effects of varied Ca and Na concentrations, and block by protons. Pore geometry, dielectric permittivity, and the number of carboxyl groups had only weak effects. The successful prediction of Ca fluxes in this paper demonstrates that ad hoc electrostatic parameters, multiple discrete binding sites, and logistic assumptions of single-file movement are all unnecessary for the prediction of permeation in Ca channels over a wide range of conditions. Further work is needed, however, to understand the atomic origin of the fixed charge, excess chemical potentials, and diffusion coefficients of the channel. The Appendix uses PNP2 theory to predict ionic currents for published "barrier-and-well" energy profiles of this channel.