Switching the ion selectivity of an ion channel on demand

离子通道是嵌入在膜中的蛋白质，当被激活时，膜打开以允许离子移动。这样的运动对生命来说是必不可少的。传统观点认为，流经任何一个通道的一种或多种离子--即所谓的离子选择性--是固定的。因此，钙通道只允许钙离子流动。钠离子通道只允许钠离子流动。而非选择性通道将允许离子组合通过。这一应用挑战了这一信念，提出离子选择性不是固定的，而是取决于打开通道的东西。该应用建立在BBSRC资助的工作基础上，该工作帮助发现了两孔通道(TPC)。TPC被认为允许从溶酶体中释放钙。溶酶体是充满酸性的结构，通常被认为是细胞的回收中心。但现在很明显，它们也是重要的钙储备。TPC已被证明控制着许多重要的功能，包括细胞周围的材料运输。他们还被认为与帕金森氏症和埃博拉病毒感染等多种疾病有关。但到底有多少钙通过它们，这些蛋白质是如何被激活的，人们对此仍有争议。考虑到它们在细胞内的位置，它们很难研究。这项拟议的工作是一项国际合作，源于两种新的打开TPC的细胞渗透药物的发现。其中一个似乎同时允许钙和钠流动，而另一个则只允许钠流动。我们进一步表明，这些药物似乎模拟了该通道的生理激活剂。因此，TPC的离子选择性可以根据需要进行改变。我们的计划是通过更好地定义TPC对不同刺激的离子选择性，计算出药物在通道中的结合位置，并使用药物选择性地影响细胞功能，来扩展这一非常不寻常的发现。我们将使用包括计算方法在内的一些实验方法来做到这一点。如果成功，我们的工作将改变我们思考离子通道如何工作的方式。我们将为许多人提供独特的资源，进一步探索TPC的功能和功能障碍。离子选择性的变化提供了一个简单的解释，为什么以前对TPC的研究得出了如此不同的结论。离子选择性随需求的变化要求对TPC进行进一步研究。

Ion channels are proteins embedded within membranes that open to allow the movement of ions when activated. Such movement is essential for life. Conventional wisdom has it that the type or types of ion that flow through any one channel - so called ion selectivity - is fixed. Thus, calcium channels will only allow calcium ions to flow. Sodium channels will only allow sodium ions to flow. And non-selective channels will allow a combination of ions to pass.This application challenges this belief by suggesting that ion selectivity is not fixed but rather that it depends on what opens the channel.It builds on work funded by the BBSRC that aided the discovery of the two-pore channels (TPCs). TPCs are thought to allow calcium to be released from lysosomes. Lysosomes are acid-filled structures that are usually considered the cell's recycling centre. But it is clear now that they are also important stores of calcium. TPCs have been shown to control many important functions including the trafficking of material around the cell. And they have been implicated in a number of diseases such as Parkinson's and Ebola infection. But exactly how much calcium passes through them and how these proteins are turned on is debated. And they are difficult to study given their location within cells.The proposed work is an international collaboration stemming from the discovery of two new cell permeable drugs that open TPCs. One of them appears to allow both calcium and sodium to flow whereas the other allows only sodium flow. We further show that these drugs seem to mimic physiological activators of the channel. The ion selectivity of TPCs can therefore be changed on demand.Our plan is to extend this highly unusual finding by better defining ion selectivity of TPCs in response to different stimuli, working out where in the channel the drugs bind and using the drugs to selectively influence cell function. We will do so using a number of experimental approaches that include computational methods.If successful, our work will change the way we think about how ion channels work. Novel chemical tools we will provide a unique resource for many to further probe function and dysfunction of TPCs. And alterations in ion selectivity offer a simple explanation for why previous studies on TPCs came to such different conclusions. Changes of ion selectivity on demand demands further study of TPCs.