title: BK Channels Alleviate Lysosomal Storage Diseases by Providing Positive Feedback Regulation of Lysosomal Ca2+ Release.
abstract: Promoting lysosomal trafficking represents a promising therapeutic approach for lysosome storage diseases. Efficient Ca(2+) mobilization from lysosomes is important for lysosomal trafficking. Ca(2+) release from lysosomes could generate a negative potential in the lumen to disturb subsequent Ca(2+) release in the absence of counter ion flux. Here we report that lysosomes express big-conductance Ca(2+)-activated potassium (BK) channels that form physical and functional coupling with the lysosomal Ca(2+) release channel, TRPML1. Ca(2+) release via TRPML1 causes BK activation, which in turn facilitates further lysosomal Ca(2+) release and membrane trafficking. Importantly, BK overexpression rescues the impaired TRPML1-mediated Ca(2+) 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 Ca(2+) 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.
authors.affiliation: Department of Physiology and Biophysics, Sir Charles Tupper Medical Building, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cao
authors.affiliation: Department of Physiology and Biophysics, Sir Charles Tupper Medical Building, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada.
authors.forename: Xi Zoë
authors.initials: XZ
authors.lastname: Zhong
authors.affiliation: Department of Physiology and Biophysics, Sir Charles Tupper Medical Building, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada.
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Zou
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology and Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7115, USA.
authors.forename: Zhu
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Division of Molecular Medicine, Department of Anesthesiology and Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-7115, USA.
authors.forename: Ligia
authors.initials: L
authors.lastname: Toro
authors.affiliation: Department of Physiology and Biophysics, Sir Charles Tupper Medical Building, Dalhousie University, 5850 College Street, Halifax, NS B3H 4R2, Canada. Electronic address: xpdong@dal.ca.
authors.forename: Xian-Ping
authors.initials: XP
authors.lastname: Dong
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005089:Exocytosis / Q000502:physiology; D025461:Feedback, Physiological; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D008062:Lipofuscin / Q000378:metabolism; D016464:Lysosomal Storage Diseases / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D000077296:Niemann-Pick C1 Protein; D010641:Phenotype; D021381:Protein Transport; D011506:Proteins / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D051036:Large-Conductance Calcium-Activated Potassium Channels; D008062:Lipofuscin; C512321:Mcoln1 protein, mouse; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D050051:Transient Receptor Potential Channels; D002118:Calcium