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

View Article: PubMed Central - PubMed

ABSTRACT

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-F408∆), 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.

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Related in: MedlinePlus

BK upregulation reduces abnormal lipofuscin accumulation in human fibroblasts carrying F408∆ but not R403C mutation.(A,B) Abnormal lipofuscin accumulation in TRPML1-F408∆ human fibroblasts and its rescue by BK overexpression. The BK rescue effect was inhibited by Syt VII DN, suggesting it depends on promoting lysosomal exocytosis. More than 35 cells were analyzed for each condition. (C,D) Abnormal lipofuscin accumulation in TRPML1-R403C human fibroblasts was not rescued by BK overexpression. More than 40 cells were analyzed for each condition.
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f5: BK upregulation reduces abnormal lipofuscin accumulation in human fibroblasts carrying F408∆ but not R403C mutation.(A,B) Abnormal lipofuscin accumulation in TRPML1-F408∆ human fibroblasts and its rescue by BK overexpression. The BK rescue effect was inhibited by Syt VII DN, suggesting it depends on promoting lysosomal exocytosis. More than 35 cells were analyzed for each condition. (C,D) Abnormal lipofuscin accumulation in TRPML1-R403C human fibroblasts was not rescued by BK overexpression. More than 40 cells were analyzed for each condition.

Mentions: Defective TRPML1 channels results in abnormal lysosomal storage, which often leads to the formation of autofluorescent lipofuscin, as seen in LSD human skin fibroblasts48. Not surprisingly, a dramatic increase in lipofuscin fluorescence was observed in human fibroblasts carrying F408∆ or R403C mutation (Fig. 5). BK overexpression significantly reduced the intensity of autofluorescence in F408∆ (Fig 5A,B), but not in R403C fibroblasts (Fig. 5C,D). Expression of Syt VII DN prohibited the rescue effect of BK overexpression on lipofuscin accumulation in F408∆ fibroblasts (Fig. 5A,B). Considering that BK upregulation promotes GECO-TRPML1-F408∆ signal, these data indicate that BK up-regulation enhances TRPML1-F408∆-mediated lysosomal exocytosis, and thereby promoting lipofuscin clearance from F408∆ fibroblasts.


BK channel agonist represents a potential therapeutic approach for lysosomal storage diseases
BK upregulation reduces abnormal lipofuscin accumulation in human fibroblasts carrying F408∆ but not R403C mutation.(A,B) Abnormal lipofuscin accumulation in TRPML1-F408∆ human fibroblasts and its rescue by BK overexpression. The BK rescue effect was inhibited by Syt VII DN, suggesting it depends on promoting lysosomal exocytosis. More than 35 cells were analyzed for each condition. (C,D) Abnormal lipofuscin accumulation in TRPML1-R403C human fibroblasts was not rescued by BK overexpression. More than 40 cells were analyzed for each condition.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5037385&req=5

f5: BK upregulation reduces abnormal lipofuscin accumulation in human fibroblasts carrying F408∆ but not R403C mutation.(A,B) Abnormal lipofuscin accumulation in TRPML1-F408∆ human fibroblasts and its rescue by BK overexpression. The BK rescue effect was inhibited by Syt VII DN, suggesting it depends on promoting lysosomal exocytosis. More than 35 cells were analyzed for each condition. (C,D) Abnormal lipofuscin accumulation in TRPML1-R403C human fibroblasts was not rescued by BK overexpression. More than 40 cells were analyzed for each condition.
Mentions: Defective TRPML1 channels results in abnormal lysosomal storage, which often leads to the formation of autofluorescent lipofuscin, as seen in LSD human skin fibroblasts48. Not surprisingly, a dramatic increase in lipofuscin fluorescence was observed in human fibroblasts carrying F408∆ or R403C mutation (Fig. 5). BK overexpression significantly reduced the intensity of autofluorescence in F408∆ (Fig 5A,B), but not in R403C fibroblasts (Fig. 5C,D). Expression of Syt VII DN prohibited the rescue effect of BK overexpression on lipofuscin accumulation in F408∆ fibroblasts (Fig. 5A,B). Considering that BK upregulation promotes GECO-TRPML1-F408∆ signal, these data indicate that BK up-regulation enhances TRPML1-F408∆-mediated lysosomal exocytosis, and thereby promoting lipofuscin clearance from F408∆ fibroblasts.

View Article: PubMed Central - PubMed

ABSTRACT

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-F408∆), 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.

No MeSH data available.


Related in: MedlinePlus