TMEM175: Lysosomal Ion Channel Physiology, Therapeutic Potential, and Emerging Pharmacology.

Abstract

Transmembrane protein 175 (TMEM175) is a lysosomal cation channel that has emerged as a promising drug target for Parkinson's disease (PD). Genetic and functional studies linking TMEM175 loss-of-function variants to increased PD risk, lysosomal dysfunction, and α-synuclein accumulation have generated considerable interest in developing pharmacological approaches to enhance channel activity. As a lysosomal cation channel with reported K+ and H+ permeability, TMEM175 regulates lysosomal membrane potential, pH stability, autophagic flux, and degradative capacity, placing it at a critical control point for cellular proteostasis. Recent advances in high-throughput screening, automated and lysosomal patch clamp electrophysiology, cryoelectron microscopy, and structure-guided medicinal chemistry have transformed TMEM175 from a relatively obscure lysosomal ion channel into a tractable drug target. These approaches have enabled the discovery of multiple classes of TMEM175 modulators while providing new insights into channel gating and mechanisms of activation. In this review, we summarize current progress in TMEM175 pharmacology, including advances in functional assay development and the emerging landscape of tool compounds used to study channel function. We discuss TMEM175 physiology and structure-function relationships, the growing evidence supporting therapeutic intervention, and recent discoveries revealing multiple mechanisms of channel activation. Finally, we highlight key challenges that remain for the field, including the development of potent and selective modulators, opportunities afforded by synergistic channel activation, and the potential application of TMEM175-directed therapeutics beyond Parkinson's disease in a broader range of neurodegenerative and lysosome-associated disorders.