1.A.78.1.1
Endosomal/Lysosomal K⁺ channel of 504 aas and 12 TMSs with two 6 TMS repeat units, KEL or TMEM175 (Cang et al. 2015).  A mutation in the encoding gene is associated with Parkinson's disease (Jing et al. 2015; Tang et al. 2023). It forms a potassium-permeable leak-like channel, which regulates lumenal pH stability and is required for autophagosome-lysosome fusion (Lee et al. 2017). It also appears to be an H⁺ channel, and pathogenesis of PD is related to lysosomal dysfunction. There is a   correlation between the lysosomal membrane protein TMEM175 and the risk of developing PD (Feng et al. 2024).  TMEM175 plays a direct and critical role in lysosomal and mitochondrial functions as well as Parkinson's Disease (PD) pathogenesis (Jinn et al. 2017). The 3-D structures of the open and closed channels are known (Oh et al. 2020). Coding variants in TMEM175 which increase the propensity for Parkinson's disease, are likely to be responsible for the association in the TMEM175/GAK/DGKQ locus, which could be mediated by affecting glucocerebrosidase activity (Krohn et al. 2020). It constitutes the major lysosomal potassium channel (Lee et al. 2017) and is the pore-forming subunit of the LysoK(GF) complex, a complex activated by extracellular growth factors (Wie et al. 2021). The LysoK(GF) complex is composed of TMEM175 and AKT (AKT1, AKT2 or AKT3). In the complex, the TMEM175 channel is opened by conformational changes in AKT, leading to its activation (Wie et al. 2021). The lysoK(GF) complex is required to protect neurons against stress-induced damage.  Hydrophobic gating, exhibited by TMEM175, is the process by which a nanopore may spontaneously dewet to form a "vapor lock" if the pore is sufficiently hydrophobic and/or narrow. This occurs without steric occlusion of the pore (Lynch et al. 2021). In addition to lysosomes, protein kinase B (PKB)-dependent regulation also influences TMEM175 currents in the plasma membrane (Pergel et al. 2021). Large-conductance Ca²⁺-activated K⁺ channel (BK) and transmembrane protein 175 (TMEM175) are the only two K⁺ channels known in lysosomes (Wu et al. 2022). Differential ion dehydration energetics explains selectivity in the non-canonical lysosomal K⁺channel, TMEM175 (Oh et al. 2022). 4-aminopyridine inhibits the lysosomal channel TMEM175 (Oh et al. 2022). TMEM175 is an evolutionarily distinct lysosomal cation channel whose mutation is associated with the development of Parkinson's disease. This protein regulates and changes in amount after cerebral ischemia (Zhang et al. 2023). The mechanism and therapeutic targets of the involvement of the lysosomal K⁺/proton channel TMEM175 in Parkinson's disease has been reported (Feng et al. 2024). This K⁺ channel in lysosomes becomes an H⁺ (hydrion) export channel with time (Feng et al. 2024).  Selective inhibitors of the lysosomal Parkinson's Disease channel, TMEM175, have been discovered (Oh et al. 2024). These inhibitors are 2-phenylpyridin-4-ylamine (2-PPA), and AP-6. Cryo-EM structures of human TMEM175 bound to 2-PPA and AP-6 reveal that they act as pore blockers, binding at distinct sites in the pore and occluding the ion permeation pathway. Acute inhibition of TMEM175 by 2-PPA or AP-6 increases the level of lysosomal macromolecule catabolism, thereby accelerating macropinocytosis and other digestive processes (Oh et al. 2024). pH regulation of TMEM175, an endolysosomal cation channel, plays a role in Parkinson's Disease (Schulze et al. 2025).  TMEM175 is both a K⁺ and an H⁺ channel (Schulze et al. 2025).