Solute Carrier Biology: Linking Transport and Signalling in the Cell.

The movement of molecules across cellular membranes is essential for life, allowing cells to exchange material with their environment, store energy, and communicate. However, membrane transport mechanisms are among the least understood aspects of cell biology and drug pharmacokinetics. The solute carrier (SLC) superfamily of integral membrane proteins are the primary gatekeepers for exchanging metabolites, drugs and ions across all biological membranes and play essential roles in nutrient sensing in the cell. The ion gradients established across membranes in our cells are unique and influence how SLCs function. How ion gradients influence SLC activity is still unknown, hampering efforts to exploit these systems to improve drug delivery and pharmacokinetics. Similarly, the mechanisms linking SLC function as nutrient receptors, or transceptors, in pathways regulating inflammation, cancer and neurodegeneration are equally obscure. This proposal addresses these two critical areas of SLC function. By applying state-of-the-art structural, biochemical, biophysical, and protein engineering methods, we will focus on how changes in proton gradients, which are critical characteristics of organelle identity, regulate transport and signalling functions in SLCs. In the long term, our research establishes the blueprint for understanding the complex relationship between transporters, ion channels and ion gradients in health and disease.