Switching the ion selectivity of an ion channel on demand

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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.