Unraveling pH Regulation of TMEM175, an Endolysosomal Cation Channel With a Role in Parkinson's Disease

Transmembrane protein 175 (TMEM175) is an endolysosomal cation channel, which has attracted much attention recently from academics and the pharmaceutical industry alike since human mutations in TMEM175 were found to be associated with the development of Parkinson's disease (PD). Thus, gain-of-function mutations were identified, which reduce and loss-of-function mutations, which increase the risk of developing PD. After having been characterized as an endolysosomal potassium channel initially, soon after TMEM175 was claimed to act as a proton channel. In fact, recent evidence suggests that depending on the conditions, TMEM175 can act as either a potassium or proton channel, without acting as an antiporter or exchanger. A recent work has now identified amino acid H57 to be directly involved in gating, increasing proton conductance of the channel while leaving the potassium conductance unaffected. We review here the current knowledge of TMEM175 function, pharmacology, physiology, and pathophysiology. We discuss the potential of this ion channel as a novel drug target for the treatment of neurodegenerative diseases such as PD, and we discuss the discovery of H57 as proton sensor.