2. Academic Validation
  3. pH regulates potassium conductance and drives a constitutive proton current in human TMEM175

pH regulates potassium conductance and drives a constitutive proton current in human TMEM175

  • Sci Adv. 2022 Mar 25;8(12):eabm1568. doi: 10.1126/sciadv.abm1568.
Wang Zheng 1,  Chen Shen 2 3,  Longfei Wang 2 3,  Shaun Rawson 2,  Wen Jun Xie 4,  Carl Nist-Lund 1,  Jason Wu 1,  Zhangfei Shen 5 6,  Shiyu Xia 2 3,  Jeffrey R Holt 1,  Hao Wu 2 3,  Tian-Min Fu 2 3 5 6
Affiliations

Affiliations

  • 1 Departments of Otolaryngology and Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 2 Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
  • 3 Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, MA 02115, USA.
  • 4 Department of Chemistry, University of Southern California, Los Angeles, CA 90089, USA.
  • 5 Department of Biological Chemistry and Pharmacology, The Ohio State University, Columbus, OH 43210, USA.
  • 6 The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
PMID: 35333573 DOI: 10.1126/sciadv.abm1568
Abstract

Human TMEM175, a noncanonical potassium (K+) channel in endolysosomes, contributes to their pH stability and is implicated in the pathogenesis of Parkinson's disease (PD). Structurally, the TMEM175 family exhibits an architecture distinct from canonical potassium channels, as it lacks the typical TVGYG selectivity filter. Here, we show that human TMEM175 not only exhibits pH-dependent structural changes that reduce K+ permeation at acidic pH but also displays proton permeation. TMEM175 constitutively conducts K+ at pH 7.4 but displays reduced K+ permeation at lower pH. In contrast, proton current through TMEM175 increases with decreasing pH because of the increased proton gradient. Molecular dynamics simulation, structure-based mutagenesis, and electrophysiological analysis suggest that K+ ions and protons share the same permeation pathway. The M393T variant of human TMEM175 associated with PD shows reduced function in both K+ and proton permeation. Together, our structural and electrophysiological analysis reveals a mechanism of TMEM175 regulation by pH.

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