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Lysosomal Ion Channels and Human Diseases
Published in Tian-Le Xu, Long-Jun Wu, Nonclassical Ion Channels in the Nervous System, 2021
Peng Huang, Mengnan Xu, Yi Wu, Xian-Ping Dong
First, TRPMLs have a role in neurodegenerative diseases. Due to its important role in lysosomal Ca2+ release and membrane trafficking, mutations in human TRPML1 cause Mucolipidosis type IV (ML-IV), a LSD with neurodegeneration and motor defects (Bassi et al., 2000; Cheng et al., 2010; Dong et al., 2008; Puertollano and Kiselyov, 2009; Sun et al., 2000; Venkatachalam et al., 2008, 2014). Impaired TRPML1 has also been implicated in several other LSDs including Niemann-Pick disease C1 (NPC1), NPA, NPB, and Fabry disease (Cao et al., 2015b; Kiselyov et al., 2010; Shen et al., 2012), and classical forms of neurodegenerative diseases including Alzheimer’s disease (Bae et al., 2014; Coen et al., 2012; Hui et al., 2019; Zhang et al., 2017) and Parkinson’s disease (Tsunemi et al., 2019). Emerging evidence further indicates that promoting TRPML1-mediated lysosomal exocytosis represents a promising therapeutic approach for LSDs (Chen et al., 2014; Medina et al., 2011; Samie and Xu, 2014; Shen et al., 2012). Compared with TRPML1, no clinically mutations in TRPML2 and TRPML3 have been reported.
TRPML Subfamily of Endolysosomal Channels
Published in Bruno Gasnier, Michael X. Zhu, Ion and Molecule Transport in Lysosomes, 2020
Nicholas E. Karagas, Morgan A. Rousseau, Kartik Venkatachalam
The mucolipin subgroup of the transient receptor potential superfamily of cation channels (TRPMLs) are evolutionarily conserved non-selective cation channels that function in endolysosomal membranes, and play key roles in the regulation of endocytosis, autophagy, and intracellular trafficking. Mammalian genomes encode three TRPML paralogs – TRPML1, TRPML2, and TRPML3 – that differ in tissue distribution and exhibit subtle, yet significant, differences in subcellular localization and molecular function. In humans, MCOLN1, which encodes TRPML1, is ubiquitously expressed, and loss-of-function mutations in this gene cause a paediatric-onset lysosomal storage disease called mucolipidosis type IV (MLIV) (Bargal et al., 2000; Bassi et al., 2000; Sun et al., 2000).
Electrophysiological Recording of a Gain-of-Function Polycystin-2 Channel with a Two-Electrode Voltage Clamp
Published in Jinghua Hu, Yong Yu, Polycystic Kidney Disease, 2019
Courtney Ng, Zhifei Wang, Bin Li, Yong Yu
Genetic studies have revealed that the linker region between S4 and S5 (S4-S5 linker) and the first half of S5 helix is a hot spot for GOF mutations of many TRP channels.23 Mutations at this region have been linked to over activity-induced channelopathies in human beings. For example, N855S in TRPA1 causes familial episodic pain syndrome,24 G573S in TRPV3 causes Olmsted syndrome,25 multiple mutations in this region of TRPV4 cause various skeletal dysplasias and motor/sensory neuropathies,26,27 and multiple mutations of TRPML1 have been found to be the underlying cause of mucolipidosis type IV.28 Some other GOF mutations of TRP channels have been generated by doing mutagenesis screens, which also fall into this region.29 These GOF mutations paved the way for scientists to study the function and regulation of these channels, especially for those that are difficult to be activated extrinsically or intrinsically.
The role of lysosomal ion channels in lysosome dysfunction
Published in Inhalation Toxicology, 2021
Rebekah L. Kendall, Andrij Holian
LSDs are marked by general lysosome dysfunction, including ion channel specific dysfunction as in the case of mucolipidosis type IV, which is a TRPML1 loss of function mutation, and Niemann-Pick disease, which is shown to have reduced TRPML1-mediated lysosomal Ca2+ release (Shen et al. 2012). Another lysosomal ion channel, the BK (a K+-specific channel), is shown to play a complementary role in TRPML1 activity in NPC1−/− cells. In NPC1−/− cells, BK overexpression promoted Ca2+ release in TRPML1 deficient cells, rescuing cholesterol accumulation and correcting membrane trafficking (Cao et al. 2015; Zhong et al. 2016). A large number of LSDs, such as Niemann-Pick and Mucolipidosis Type IV, are characterized by progressive neurodegeneration indicating a close association between lysosomal dysfunction and neurodegenerative disease (Nixon 2013; Perera and Zoncu 2016; Platt et al. 2018).