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-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.
Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada.
Xi Zoë
XZ
Zhong
Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada.
Xue
X
Sun
Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada.
Qi
Q
Cao
Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada.
Gaofeng
G
Dong
Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA.
Raphael
R
Schiffmann
Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada.
Xian-Ping
XP
Dong
Dev Cell. 2013 Sep 16;26(5):511-24
23993788
Dev Cell. 2011 Sep 13;21(3):421-30
21889421
J Inherit Metab Dis. 2014 Nov;37(6):1013-22
24850378
J Cell Biol. 2012 Nov 26;199(5):723-34
23185029
J Biol Chem. 2010 Jul 2;285(27):20423-7
20430897
Trends Neurosci. 2014 Feb;37(2):66-76
24411104
J Cell Sci. 2010 Sep 15;123(Pt 18):3112-24
20736310
J Cell Biol. 2012 Jul 9;198(1):23-35
22753898
J Biol Chem. 2014 Aug 15;289(33):23189-99
24962569
Cell Mol Life Sci. 2013 Aug;70(16):2919-34
23132096
Nat Rev Mol Cell Biol. 2007 Aug;8(8):622-32
17637737
Science. 2011 Sep 30;333(6051):1888-91
21903779
Nat Rev Neurosci. 2005 Sep;6(9):713-25
16049428
Free Radic Biol Med. 2002 Sep 1;33(5):611-9
12208347
Biochem J. 2011 Nov 1;439(3):349-74
21992097
Cell Calcium. 2015 Jul;58(1):48-56
25465891
Nat Med. 2008 Nov;14(11):1247-55
18953351
Front Physiol. 2014 Oct 09;5:389
25346695
Nat Rev Mol Cell Biol. 2009 Sep;10(9):623-35
19672277
Dev Cell. 2015 May 26;33(4):427-41
25982675
Int J Alzheimers Dis. 2012;2012:752894
22970406
Cell. 2001 Jul 27;106(2):157-69
11511344
Acta Biochim Biophys Sin (Shanghai). 2009 Jun;41(6):437-45
19499146
J Biol Chem. 2011 Jul 1;286(26):22934-42
21540176
Cell Calcium. 2010 Feb;47(2):103-11
20053447
Mol Genet Metab. 2006 Dec;89(4):339-48
16914343
Br J Psychiatry. 1982 Feb;140:142-8
7074296
Brain. 2008 Aug;131(Pt 8):1969-78
18187492
Science. 2013 Feb 15;339(6121):819-23
23287718
Nature. 2008 Oct 16;455(7215):992-6
18794901
Nat Commun. 2014 Aug 14;5:4681
25119295
Circulation. 2014 Sep 23;130(13):1081-90
25245844
J Lipid Res. 2014 Jun;55(6):995-1009
24668941
Proc Natl Acad Sci U S A. 2012 Feb 28;109(9):3552-7
22331907
Cell Calcium. 2011 Aug;50(2):200-5
21724254
J Neurosci. 2014 Aug 20;34(34):11485-503
25143627
J Biol Chem. 2009 Nov 13;284(46):32040-52
19638346
Neuroscience. 2006 Oct 27;142(3):661-9
16908104
Nat Commun. 2012 Mar 13;3:731
22415822
Nat Med. 2014 Oct;20(10):1187-92
25216637