Journal
DEVELOPMENTAL CELL
Volume 33, Issue 4, Pages 427-441Publisher
CELL PRESS
DOI: 10.1016/j.devcel.2015.04.010
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Funding
- Department of Physiology and Biophysics, Dalhousie University
- Dalhousie Medical Research Foundation (DMRF) Equipment Grant
- DMRF New Investigator Award
- Canadian Institutes of Health Research (CIHR) [MOP-119349]
- CIHR New Investigator Award [201109MSH-261462-208625]
- Nova Scotia Health Research Foundation Establishment Grant [MED-PRO-2011-7485]
- Canada Foundation for Innovation Leaders Opportunity Fund-Funding for Research Infrastructure [29291]
- NIH RO1 grant [HL107418]
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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.
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