BK channel agonist represents a potential therapeutic approach for lysosomal storage diseases

Efficient lysosomal Ca²⁺ release plays an essential role in lysosomal trafficking. We have recently shown that lysosomal big conductance Ca²⁺ -activated potassium (BK) channel forms a physical and functional coupling with the lysosomal Ca²⁺ release channel Transient Receptor Potential Mucolipin-1 (TRPML1). BK and TRPML1 forms a positive feedback loop to facilitate lysosomal Ca²⁺ release and subsequent lysosome membrane trafficking. However, it is unclear whether the positive feedback mechanism is common for other lysosomal storage diseases (LSDs) and whether BK channel agonists rescue abnormal lysosomal storage in LSDs. In this study, we assessed the effect of BK agonist, NS1619 and NS11021 in a number of LSDs including NPC1, mild cases of mucolipidosis type IV (ML4) (TRPML1-F408Δ), Niemann-Pick type A (NPA) and Fabry disease. We found that TRPML1-mediated Ca²⁺ release was compromised in these LSDs. BK activation corrected the impaired Ca²⁺ release in these LSDs and successfully rescued the abnormal lysosomal storage of these diseases by promoting TRPML1-mediated lysosomal exocytosis. Our study suggests that BK channel activation stimulates the TRPML1-BK positive reinforcing loop to correct abnormal lysosomal storage in LSDs. Drugs targeting BK channel represent a potential therapeutic approach for LSDs.