Linking the lipid-sensing TMEM16A channel with lysosomal lipid storage mechanisms: implications for drug discovery

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We run on electricity - virtually all vital functions like the beating of the heart, the activity of our brain, the function of blood vessels or muscle contractions are triggered by tiny electrical currents that occur through the surface (membrane) of each cell. Responsible for these currents are ion channels, proteins that form microscopic gated pores that selectively allow charged ions to move in and out of the cell; the electrical impulses they generate initiate the vast array of events indispensable for life, such as those mentioned above.A class of ion channels that are found in many cell types in the body are those that allow chloride ions to move across the membrane. For example, these chloride channels are found in the muscle cells that line blood vessels. When the channel is open, chloride "currents" are activated and the blood vessel contracts; when the channel is closed, the current is suppressed and the blood vessel is relaxed. In this way, the blood can be directed to various parts of the body depending on the need. One special feature of this channel is that its opening and closing is regulated by the membrane itself. The membrane is made of oily substances (such as cholesterol) and changes in the composition of the "oils" (technically "lipids") that make up the membrane can affect the function of these chloride channels and, as a consequence, affect many aspects of body biology. The lipid composition itself is controlled by other cellular compartments such as the lysosome that is a specialised part of the cell. We have discovered that if lysosomes are not working properly, the chloride channels are also affected. We now want to understand exactly how this happens and make use of this new knowledge to design new molecules that could eventually be used to control the function of the chloride channels and address many diseases such as those involving blood vessels (e.g. high blood pressure, stroke etc.) and generally diseases in which lipid content is altered (such as a debilitating rare genetic disease known as Niemann-Pick disease type C).To achieve this ambitious aim, we will use a variety of techniques from measurement of the passage of ions in single cells (when the membrane is normal or altered) to genetic modifications of the chloride channel. Importantly, we will combine our expertise in cellular biology with that of colleagues in Industry, who have specific skills in discovering and developing new medicines. Our work will shed light on new aspects of cell biology and, in the longer term, lead to the generation of new medicines.