Characterising the relationship between structural changes and ion channel function of TRPC4/TRPC5 through site directed mutagenesis studies

Abstract

Pain is a vital and protective mechanism to avoid the cause of harmful stimuli. However, pain can become a disease which is not beneficial for the individual, this is called chronic pain. Chronic pain is a worldwide issue, with a lack of effective non-opioid based treatments. Moreover, the exact mechanism of chronic pain is not well understood. As a result, more research is needed within the field of pain to increase the knowledge and to find better treatments for chronic pain. This project will study Ca2+-permeable non-selective cation channels called TRPCs, more specifically TRPC4 and TRPC5. The aim of the project is to understand how structural changes affect the function. This will be achieved through inducing point mutations in one of the two antagonist binding pockets of TRPC4/TRPC5. The study will investigate how the mutations affect the function of TRPC4/TRPC5 and how they affect agonist and antagonist interactions with TRPC4/TRPC5. The mutation studies are especially important to get a better understanding of how TRPC4/TRPC5 interact with the antagonist and which amino acids are important for the interaction. These studies could aid drug design to find non-opioid based drug against pain targeting TRPC4/TRPC5.