BK Channels Alleviate Lysosomal Storage Diseases by Providing Positive Feedback Regulation of Lysosomal Ca2+ Release

Promoting lysosomal trafficking represents a promising therapeutic approach for lysosome storage diseases. Efficient Ca2+ mobilization from lysosomes is important for lysosomal trafficking. Ca2+ release from lysosomes could generate a negative potential in the lumen to disturb subsequent Ca2+ release in the absence of counter ion flux. Here we report that lysosomes express big-conductance Ca2+-activated potassium (BK) channels that form physical and functional coupling with the lysosomal Ca2+ release channel, TRPML1. Ca2+ release via TRPML1 causes BK activation, which in turn facilitates further lysosomal Ca2+ release and membrane trafficking. Importantly, BK overexpression rescues the impaired TRPML1-mediated Ca2+ release and abnormal lysosomal storage in cells from Niemann-Pick C1 patients. Therefore, we have identified a lysosomal K+ channel that provides a positive feedback mechanism to facilitate TRPML1-mediated Ca2+ release and membrane trafficking. Our findings suggest that upregulating BK may be a potential therapeutic strategy for certain lysosomal storage diseases and common neurodegenerative disorders.