Schulze Tobias, Rauh Oliver, Thiel Gerhard, Fertig Niels, Bazzone Andre, Grimm Christian
Walther Straub Institute of Pharmacology and Toxicology, Faculty of Medicine, Ludwig-Maximilians-University, Munich, Germany.
Department of Natural Sciences, Institute for Functional Gene Analytics, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany.
J Cell Physiol. 2025 Feb;240(2):e70008. doi: 10.1002/jcp.70008.
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.
跨膜蛋白175（TMEM175）是一种内溶酶体阳离子通道，自从发现TMEM175的人类突变与帕金森病（PD）的发生有关以来，它最近引起了学术界和制药行业的广泛关注。因此，发现了功能获得性突变，这些突变会降低患PD的风险，而功能丧失性突变则会增加患PD的风险。最初，TMEM175被表征为一种内溶酶体钾通道，之后不久又有人声称它可作为质子通道。事实上，最近的证据表明，根据不同条件，TMEM175既可以作为钾通道，也可以作为质子通道，而不是作为反向转运体或交换体。最近的一项研究现已确定氨基酸H57直接参与门控，增加了通道的质子传导性，而不影响钾传导性。我们在此回顾目前关于TMEM175功能、药理学、生理学和病理生理学的知识。我们讨论了这种离子通道作为治疗诸如PD等神经退行性疾病的新型药物靶点的潜力，并且我们讨论了H57作为质子传感器的发现。
