Transmembrane Protein 175, a Lysosomal Ion Channel Related to Parkinson's Disease

Lysosomes are membrane-bound organelles with an acidic lumen and are traditionally characterized as a recycling center in cells. Lysosomal ion channels are integral membrane proteins that form pores in lysosomal membranes and allow the influx and efflux of essential ions. Transmembrane protein 175 (TMEM175) is a unique lysosomal potassium channel that shares little sequence similarity with other potassium channels. It is found in bacteria, archaea, and animals. The prokaryotic TMEM175 consists of one six-transmembrane domain that adopts a tetrameric architecture, while the mammalian TMEM175 is comprised of two six-transmembrane domains that function as a dimer in lysosomal membranes. Previous studies have demonstrated that the lysosomal K⁺ conductance mediated by TMEM175 is critical for setting membrane potential, maintaining pH stability, and regulating lysosome-autophagosome fusion. AKT and B-cell lymphoma 2 regulate TMEM175's channel activity through direct binding. Two recent studies reported that the human TMEM175 is also a proton-selective channel under normal lysosomal pH (4.5-5.5) as the K⁺ permeation dramatically decreased at low pH while the H⁺ current through TMEM175 greatly increased. Genome-wide association studies and functional studies in mouse models have established that TMEM175 is implicated in the pathogenesis of Parkinson's disease, which sparks more research interests in this lysosomal channel.