Parkinson’s: ion channel as promising avenue for new drugs

All washbasins, bathtubs and sinks have overflow protection to prevent water from spilling over the edge of the basin. Such a safety mechanism also exists in the recycling centres of human cells. This is shown by a new study by researchers from Hochschule Bonn-Rhein-Sieg, LMU Munich, TU Darmstadt and the company Nanion Technologies, which has now been published in the scientific journal PNAS (Proceedings of the National Academy of Sciences). "The ion channel TMEM175 presumably takes on the role of an overflow valve in lysosomes, which prevents excessive acidification," says Dr Oliver Rauh, research associate at H-BRS. Together with Professor Christian Grimm (LMU Munich), he is the corresponding author of the study. The researchers have used electrophysiological and bioinformatic methods to decipher the previously controversial function of this ion channel. An ion channel is a protein that is embedded in biological membranes and enables their permeability for electrically charged particles (ions).

Fine adjustment of the acidic pH value in lysosomes

Lysosomes are small, membrane-enclosed vesicles that take on the function of recycling centres in human cells - meaning that they break down macromolecules such as proteins, polysaccharides and nucleic acids into their basic building blocks. These degradation reactions inside the lysosomes are made possible by enzymes known as hydrolases. The prerequisite for this is an acidic pH value. The pH value is nothing more than a measure of the concentration of protons in an aqueous solution. The lower the pH value, the higher the proton concentration. To keep the inside of the lysosomes acidic, a transmembrane protein, the so-called V-ATPase, pumps protons into the lysosomes. However, the fine adjustment of the pH value depends on other proteins located in the lysosomal membrane. The work published in PNAS now demonstrates the crucial role of TMEM175.

Channel protein TMEM175 conducts potassium ions and protons

Background: The cellular localisation and function of the ion channel TMEM175 was unknown for a long time, which is reflected in its meaningless name: TMEM175 simply stands for transmembrane protein 175. In recent years, it has increasingly become the focus of research as its role in the occurrence of various neurodegenerative diseases, and Parkinson's in particular, has crystallised. In the meantime, several studies have proven beyond doubt that TMEM175 is a channel protein that conducts ions through the membrane of lysosomes. However, researchers could not agree on the question of whether this channel primarily conducts potassium ions (K⁺) or protons (H⁺) and what function the corresponding ion fluxes have in lysosomes of healthy and diseased cells.

Specific pH sensor inside the lysosome

"I have worked on many ion channels, but TMEM175 is by far the strangest of them all," says Dr Oliver Rauh, who moved from TU Darmstadt to H-BRS to work in the DFG research network "CytoTransport". "When we started the project around six years ago, it was assumed that TMEM175 was a potassium channel. Its function was completely unknown. We have now been able to show that TMEM175 not only conducts potassium ions, but also protons and is therefore directly involved in the regulation of the pH value, i.e. the proton concentration, inside lysosomes." The researchers demonstrated that the ion channel has a specific pH sensor that faces the inside of the lysosome. In this way, TMEM175 can recognise the critical acid status and adjust the proton flow through the ion channel accordingly.