Levitan I B
Graduate Department of Biochemistry, Brandeis University, Waltham, Massachusetts 02254.
Annu Rev Physiol. 1994;56:193-212. doi: 10.1146/annurev.ph.56.030194.001205.
Modulation of the properties of membrane ion channels is of fundamental importance for the regulation of neuronal electrical activity and of higher neural functions. Among the many potential molecular mechanisms for modulating the activity of membrane proteins such as ion channels, protein phosphorylation has been chosen by cells to play a particularly prominent part. This is not surprising given the central role of protein phosphorylation in a wide variety of cellular, metabolic, and signaling processes (26, 27, 48). As summarized here, regulation by phosphorylation is not restricted to one or another class of ion channel; rather, many, and perhaps all, ion channels are subject to modulation by phosphorylation. Similarly, a number of different protein kinase signaling pathways can participate in the regulation of ion channel properties, and it is not unusual to find that a particular channel is modulated by several different protein kinases, each influencing channel activity in a unique way. Finally, the biophysical mechanisms of modulation also exhibit a striking diversity that ranges from changes in desensitization rates to shifts in the voltage dependence and kinetics of channel activation and inactivation. The convergence of channel molecular biology with patch-clamp technology has been spectacularly productive, even allowing the identification of particular amino acid residues in ion channel proteins that participate in specific modulatory changes in channel biophysical properties. This task is far from complete, and no doubt there remain surprises in store for us, but nevertheless it is appropriate to ask where we go from here. One important direction will be to relate functional modulation, produced by phosphorylation, to changes in the three-dimensional structure of the ion channel protein. Unfortunately, structural studies of membrane proteins are extremely difficult, and to date there is no high resolution structure available for any ion channel protein. A complementary strategy that is more feasible with current technology is to investigate the ways in which channel modulation contributes to the regulation of cellular physiology. Novel computational approaches are being brought to bear on this complex issue, and their combination with channel molecular biology and biophysics should significantly advance our understanding of molecular mechanisms of neuronal plasticity.
膜离子通道特性的调节对于神经元电活动及更高层次神经功能的调控至关重要。在众多调节膜蛋白（如离子通道）活性的潜在分子机制中，细胞选择了蛋白磷酸化发挥特别突出的作用。鉴于蛋白磷酸化在多种细胞、代谢和信号传导过程中所起的核心作用（26、27、48），这并不令人惊讶。如下所述，磷酸化调节并不局限于某一类离子通道；相反，许多甚至可能所有的离子通道都受到磷酸化的调节。同样，多种不同的蛋白激酶信号通路可参与离子通道特性的调节，并且常常会发现一个特定的通道受到几种不同蛋白激酶的调节，每种激酶以独特的方式影响通道活性。最后，调节的生物物理机制也呈现出惊人的多样性，从脱敏速率的变化到通道激活和失活的电压依赖性及动力学的改变。通道分子生物学与膜片钳技术的结合成果斐然，甚至能够鉴定出离子通道蛋白中参与通道生物物理特性特定调节变化的特定氨基酸残基。这项任务远未完成，无疑仍有惊喜等待着我们，但无论如何，我们应该问问接下来该何去何从。一个重要的方向将是将磷酸化产生的功能调节与离子通道蛋白的三维结构变化联系起来。不幸的是，膜蛋白的结构研究极其困难，迄今为止尚无任何离子通道蛋白的高分辨率结构。当前技术下更可行的一种互补策略是研究通道调节对细胞生理学调控的作用方式。新的计算方法正被应用于这个复杂的问题，它们与通道分子生物学和生物物理学的结合应能显著推进我们对神经元可塑性分子机制的理解。
