Zhong Xi Zoë, Sun Xue, Cao Qi, Dong Gaofeng, Schiffmann Raphael, Dong Xian-Ping
Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Medical Building, 5850 College Street, Halifax, B3H 4R2, Nova Scotia, Canada.
Institute of Metabolic Disease, Baylor Research Institute, 3812 Elm Street, Dallas, TX, 75226, USA.
Sci Rep. 2016 Sep 27;6:33684. doi: 10.1038/srep33684.
Efficient lysosomal Ca release plays an essential role in lysosomal trafficking. We have recently shown that lysosomal big conductance Ca-activated potassium (BK) channel forms a physical and functional coupling with the lysosomal Ca release channel Transient Receptor Potential Mucolipin-1 (TRPML1). BK and TRPML1 forms a positive feedback loop to facilitate lysosomal Ca 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 Ca release was compromised in these LSDs. BK activation corrected the impaired Ca 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.
高效的溶酶体钙释放对溶酶体运输起着至关重要的作用。我们最近发现，溶酶体大电导钙激活钾（BK）通道与溶酶体钙释放通道瞬时受体电位黏脂素1（TRPML1）形成了物理和功能上的偶联。BK和TRPML1形成一个正反馈环，以促进溶酶体钙释放及随后的溶酶体膜运输。然而，尚不清楚这种正反馈机制是否在其他溶酶体贮积病（LSDs）中普遍存在，以及BK通道激动剂是否能挽救LSDs中的异常溶酶体贮积。在本研究中，我们评估了BK激动剂NS1619和NS11021对多种LSDs的影响，包括尼曼-皮克病C型1（NPC1）、IV型黏脂贮积症（ML4）（TRPML1-F408∆）轻症病例、A型尼曼-皮克病（NPA）和法布里病。我们发现这些LSDs中TRPML1介导的钙释放受损。BK激活纠正了这些LSDs中受损的钙释放，并通过促进TRPML1介导的溶酶体外排成功挽救了这些疾病的异常溶酶体贮积。我们的研究表明，BK通道激活刺激TRPML1-BK正反馈环，以纠正LSDs中的异常溶酶体贮积。靶向BK通道的药物代表了一种治疗LSDs的潜在方法。
