VanDongen Antonius M J
Department of Pharmacology, Duke University, Durham, NC 27710, USA.
Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3248-52. doi: 10.1073/pnas.0308743101. Epub 2004 Feb 19.
A universal property of ion channels is their ability to alternate stochastically between two permeation states, open and closed. This behavior is thought to be controlled by a steric "gate", a structure that physically impedes ion flow in the closed state and moves out of the way during channel opening. Experiments employing macroscopic currents in the Shaker K channel have suggested a cytoplasmic localization for the gate. Crystallographic structures of the KcsA K channel indeed reveal a cytoplasmic constriction, implying that the gate and selectivity filter are localized to opposite ends of the permeation pathway. However, analysis of K channel subconductance behavior has suggested a strict coupling between channel opening (gating) and permeation. The idea that the selectivity filter is the gate was therefore investigated by using Monte Carlo simulations. Gating is accomplished by allowing the filter to alternate stochastically between two conformations: a high-affinity state, which selectively binds K ions (but not Na ions) and traps them, and a completely nonselective, low-affinity state, which allows both Na and K ions to permeate. The results of these simulations indicate that affinity switching not only endows the selectivity filter with gating abilities, it also allows efficient permeation without jeopardizing ion selectivity. In this model, permeation and gating result from the same process.
离子通道的一个普遍特性是它们能够在开放和关闭这两种通透状态之间随机交替。这种行为被认为是由一个空间“门”控制的，该结构在关闭状态下物理性地阻碍离子流动，并在通道开放时移开。利用摇蚊钾通道中的宏观电流进行的实验表明门位于细胞质中。钾离子通道KcsA的晶体结构确实揭示了一个细胞质收缩区域，这意味着门和选择性过滤器位于通透途径的相对两端。然而，对钾通道亚电导行为的分析表明通道开放（门控）和通透之间存在严格的耦合。因此，通过使用蒙特卡罗模拟研究了选择性过滤器是门的这一观点。门控是通过允许过滤器在两种构象之间随机交替来实现的：一种高亲和力状态，它选择性地结合钾离子（但不结合钠离子）并捕获它们；另一种完全非选择性的低亲和力状态，它允许钠离子和钾离子都通透。这些模拟结果表明，亲和力切换不仅赋予选择性过滤器门控能力，还能在不损害离子选择性的情况下实现高效通透。在这个模型中，通透和门控源于同一过程。
