Transmembrane protein 175 (TMEM175)

Transmembrane protein 175 (TMEM175) is a lysosomal ion channel that has a pivotal role in maintaining lysosomal membrane potential and pH homeostasis. Unlike canonical potassium channels, TMEM175 is evolutionarily distinct and lacks the typical selectivity filter, instead forming a unique homodimeric/pseudo-tetrameric architecture to conduct ions across the lysosomal membrane. TMEM175 functions as both a potassium-selective and a proton-selective channel, with the balance between these conductances determined by the lysosomal pH; it serves as a major K⁺ channel under neutral conditions but preferentially conducts protons under acidic conditions such as those found in lysosomes. The channel is critical for termination of excessive acidification by mediating a pH-activated proton leak, ensuring optimal lysosomal acidification for degradative functions. TMEM175 genetic variants are strongly associated with Parkinson’s disease risk, and its dysfunction is linked to impaired lysosomal activity, aggregation of α-synuclein, and altered neurodegeneration susceptibility. Pharmacological inhibitors like 4-aminopyridine and potential endogenous or synthetic modulators are under investigation for their ability to modulate TMEM175 activity for therapeutic purposes.

Other names

Endosomal/lysosomal proton channel TMEM175hTMEM175MGC4618Potassium channel TMEM175Endosomal/lysosomal potassium channel TMEM175

4-Aminopyridine: small-molecule inhibition by binding near the center of the open-state channel, blocking K⁺/H⁺ conduction; Agonists: activation of proton conductance to facilitate lysosomal pH regulation