A voltage-dependent K+ channel in the lysosome is required for refilling lysosomal Ca2+ stores

The resting membrane potential (Delta psi) of the cell is negative on the cytosolic side and determined primarily by the plasma membrane's selective permeability to K+. We show that lysosomal Delta psi is set by lysosomal membrane permeabilities to Na+ and H+, but not K+, and is positive on the cytosolic side. An increase in juxta-lysosomal Ca2+ rapidly reversed lysosomal Delta psi by activating a large voltage-dependent and K+-selective conductance (LysoK(VCa)). LysoK(VCa) is encoded molecularly by SLO1 proteins known for forming plasma membrane BK channels. Opening of single LysoK(VCa) channels is sufficient to cause the rapid, striking changes in lysosomal Delta psi. Lysosomal Ca2+ stores may be refilled from endoplasmic reticulum (ER) Ca2+ via ER-lysosome membrane contact sites. We propose that LysoK(VCa) serves as the perilysosomal Ca2+ effector to prime lysosomes for the refilling process. Consistently, genetic ablation or pharmacological inhibition of LysoK(VCa), or abolition of its Ca2+ sensitivity, blocks refilling and maintenance of lysosomal Ca2+ stores, resulting in lysosomal cholesterol accumulation and a lysosome storage phenotype.