1.A.78 The K⁺-selective Channel in Endosomes and Lysosomes (KEL) Family 

Organelle K⁺ conductance studies revealed a major K⁺-selective channel, KEL or TMEM175, on endosomes and lysosomes (Cang et al. 2015). Unlike any of the approximately 80 plasma membrane K⁺ channels in mammals, TMEM175 has two repeats of 6 TMSs and has no GYG K⁺ channel sequence signature in a pore (P) loop. Lysosomes lacking TMEM175 exhibit no K⁺ conductance, have a markedly depolarized Δpsi and little sensitivity to changes in [K⁺]. These mutants have compromised luminal pH stability and abnormal fusion with autophagosomes during autophagy. Thus, TMEM175 comprises a K⁺ channel that underlies the molecular mechanism of lysosomal K⁺ permeability (Cang et al. 2015). Wu et al. 2023 have reviewed the research progress on the structural, modulatory, and functional properties of TMEM175. Wang et al. 2025 reviewed the structure, composition, and function of TMEM175 with respect to its relationship with Parkinson's disease (PD).

TMEM175 establishes a membrane potential essential for lysosomal function, and its dysregulation is associated with the development of Parkinson's Disease. It is evolutionarily distinct from all other known channels, predicting novel ion-selectivity and gating mechanisms. Oh et al. 2020 presented cryo-EM structures of human KEL in open and closed conformations at resolutions of up to 2.6 Å. It adopts a homodimeric architecture with a central ion-conduction pore lined by the side chains of the pore-lining helices. Conserved isoleucine residues in the center of the pore serve as the gate in the closed conformation. In the widened channel in the open conformation, these same residues establish a constriction essential for K⁺ selectivity (Oh et al. 2020). 4-Aminopyridine inhibits the lysosomal TMEM175 channel (Oh et al. 2022).

The generalized reaction catalyzed by KEL is:

K⁺ (in the lumen of an endosome or lysosome) ⇌ K⁺ (cytoplasm)