Structural insights into TRPM ion channels by means of Clotrimazole based chemical probes

Cells in the body communicate with each other and with their surroundings in various ways. One way is by using specific channels that let ions (components of salt) pass through the cell membrane. Just as the gates in a castle are not always unlocked, most channels open only upon a certain stimulus. In this way, we can experience temperature changes or transmit signals in our nervous system. The so-called TRP ion channel subfamily M is expressed in sensory neurons and plays a role in the detection of pain. Their members have potential as therapeutic targets, but a lack in understanding their structure and mechanism prevents development of drugs. In recent cell biology research, it was discovered that one member of this family, TRPM3, interacts with Clotrimazole (Clt), a wellknown antifungal. Upon Clt interaction, the TRPM3 seems to open a second pore, but details are unclear. In this research, we will use a combination of chemical synthesis, cell biology testing and analytical chemistry. The aim is to make a Clt-like molecule that can modify the protein at the site of binding. Sophisticated protein analysis and mass spectrometry will then allow to determine how the Clt-like molecule binds to the TRPM3. This will open new ways of studying this specific channel and provide new chemical techniques to find out how molecules bind to other ion channels. This increased knowledge will contribute to the future design and development of therapeutics against these channels.