Structural studies of heteromeric TRPC1/4/5 channels to unravel the role of the modulatory TRPC1 subunit

The cells in our bodies communicate with their environment and with neighbouring cells through the transmission of information across the cell membrane, which separates the cellular content from the extracellular environment. One major mechanism of communication is the movement across cell membranes of ions - mainly sodium, potassium, calcium and chloride - through protein molecules called ion channels.

Ion channels have key roles in physiology and many human diseases result from or are made worse by abnormal function of ion channels. Indeed, many successful therapeutic drugs work by activating or blocking ion channels. Despite the significant increase in our understanding of the 3-dimensional structures of ion channels, underpinned by recent developments in electron microscopy, we still face major knowledge gaps that hinder our understanding of their biological mechanisms and limit our ability to design effective drug candidates.

An important class of ion channels is formed by the 28 different proteins of the Transient Receptor Potential (TRP) family, with each channel made up of four TRP proteins (or potentially five in some cases/circumstances). A prominent example is the capsaicin receptor/heat sensor TRPV1 (topic of the Nobel Prize in Physiology & Medicine 2021). Our research focuses on the related TRPC ion channels, and especially those formed by the proteins called TRPC1, TRPC4 and TRPC5.

TRPC1/4/5 channels are important players in biology and are being tested in the clinic as potential new targets for the treatment of major depressive and post-traumatic stress disorders. In addition, TRPC1/4/5 channels are thought to be mediators for diseases of the heart, blood vessels and kidneys, as well as some forms of cancer.

In the body, TRPC1/4/5 channels consist of different combinations of TRPC1, TRPC4 and TRPC5 proteins. Importantly, the TRPC1 component gives these channels unique properties, but despite >20-years of research, we have limited understanding of how it does this. We and others have previously studied the structures of TRPC4 and TRPC5 channels, revealing many aspects of their function and interactions with drug-like substances. However, the structures of TRPC1-containing channels have not been determined so far.

In this project, we will make use of Leeds' cryo-electron microscopy facility (>£22m investment in state-of-the-art equipment, support staff and training since 2015) to determine the first 3-dimensional structures of TRPC1/4/5 channels that incorporate the TRPC1 subunit. In addition, we will investigate which parts of TRPC1 give it its special function by making small changes to the protein and measuring activities of resulting channels in cells.

This work will provide the first detailed 3-dimensional models of how TRPC1-containing channels form and how TRPC1 contributes to their unique properties and interactions with drug-like molecules. We expect that such new fundamental insights into this fascinating family of biological molecules will allow more precise design of new therapeutic drugs.