Structure and Function of a Bacterial Na Channel

描述(申请人提供)：离子通道控制着思考的大脑、跳动的心脏、收缩的肌肉和身体的每一个细胞的活动。它们是许多治疗药物的靶标；离子通道基因的突变是数十种遗传性疾病的原因，包括心律失常和神经疾病。这些离子通道中的许多都是为了响应细胞膜上电压的变化而打开的。这一建议的中心长期目标是了解离子通道电压门控的分子机制。我们最近在细菌中发现了一种离子通道(NaChBac)，它具有人类一类重要的离子通道的许多特性：它选择性地对钠离子通道，通过改变膜电压来开放(门控)，并在电压依赖门后以时间依赖的方式失活。NaChBac是唯一可以在哺乳动物细胞系中表达和研究的电压依赖性离子通道。这一点很重要，因为细菌通道是最有可能为高分辨率结构研究(X射线结晶学)提供足够蛋白质的来源。NaChBac蛋白已经结晶，很可能产生高分辨率的结构数据。因此，通过诱变和电生理相结合的研究来研究这种离子通道的结构和功能是至关重要的。获得的关于其离子选择性、电压门控和失活的信息可以在获得时直接与结构相关。了解这个相对简单的离子通道将有助于我们了解更大类别的通道是如何发挥作用的，以及最终我们如何将它们作为治疗剂的靶点。

DESCRIPTION (provided by applicant): Ion channels govern the activity of the thinking brain, beating heart, contracting muscle, and every cell of the body. They are targets of many therapeutic agents; mutations of ion channel genes are the cause of dozens of inherited diseases, including cardiac arrhythmias and neurological illnesses. Many of these ion channels are opened in response to changes in voltage across the cell membrane. The central long-term aim of this proposal is to understand the molecular mechanism of voltage gating of ion channels. We recently discovered an ion channel in bacteria (NaChBac) that has many of the properties of an important class of ion channels in humans: it is selectively permeant to sodium, opened (gated) by changes in membrane voltage, and inactivated in a time-dependant manner after voltage-dependant gating.NaChBac is unique in being the only voltage-dependent ion channel that can be expressed and studied in a mammalian cell line. This is important because bacterial channels are the most likely sources of sufficient protein for high-resolution structural studies (X-ray crystallography). The NaChBac protein has been crystallized and is likely to yield high-resolution structural data. It is thus crucial to investigate the structure and function of this ion channel through a combination of mutagenic and electrophysiologic studies. Information gained about its ion selectivity, voltage gating, and inactivation can then be directly correlated to the structure when obtained. Understanding this relatively simple ion channel will help us understand how the larger class of channels function, and eventually how we might target them with therapeutic agents.