Role of TRPML and Two-Pore Channels in Endolysosomal Cation Homeostasis

Grimm, Christian; Hassan, Sami; Wahl‐Schott, Christian; Biel, Martin

doi:10.1124/jpet.112.192880

Cited by 74 publications

(57 citation statements)

References 90 publications

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“…In addition, all TRPML channels can be activated by the endogenous compound PI(3,5)P 2 (1, 38 -41). This points to common activation mechanism(s) for all three TRPML channels, at least with regard to some of the identified small chemical activators and PI(3,5)P 2 (41).…”

Section: Discussionmentioning

confidence: 80%

Constitutive Activity of TRPML2 and TRPML3 Channels versus Activation by Low Extracellular Sodium and Small Molecules

Jörs

Guo²,

Obukhov³

et al. 2012

Journal of Biological Chemistry

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Background: Physiological function(s) and activation mechanism(s) of TRPML2 and TRPML3 channels are largely unknown. Results: TRPML2 and TRPML3 channels are activated by different small chemical compounds and low extracellular sodium. Mutations in the first and second extracellular loops render TRPML3 constitutively active in high extracellular sodium. Conclusion: TRPML2 and TRPML3 display similar activation mechanisms. Significance: Novel insights into TRPML2 and TRPML3 activation are provided.

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Section: Discussionmentioning

confidence: 80%

Constitutive Activity of TRPML2 and TRPML3 Channels versus Activation by Low Extracellular Sodium and Small Molecules

Jörs

Guo²,

Obukhov³

et al. 2012

Journal of Biological Chemistry

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“…The channel pore of TRPML1 is formed by the pore-loop region between the S5 and S6 domains, which are presumed to form the channel gate (83). Whereas TRPML1 is ubiquitously expressed in every tissue and cell type, TRPML2 and TRPML3 are expressed only in special cell types (83, 87). …”

Section: Trpml Channelsmentioning

confidence: 99%

“…TRPML1–3 channels are predominantly (>75%) localized on LEL membranes, but heterologously expressed TRPML1 proteins are also detected in the early endosomes and plasma membranes (83, 87). Two dileucine motifs located separately in the N- and C- cytosolic tails are responsible for the LEL localization through a direct, AP1/3-dependent, TGN-LEL trafficking pathway and through an indirect, AP2-dependent, TGN–plasma membrane–LEL pathway (88--90).…”

Section: Trpml Channelsmentioning

confidence: 99%

Lysosomal Physiology

Ren

2015

Annu. Rev. Physiol.

818

749

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Lysosomes are acidic compartments filled with more than 60 different types of hydrolases. They mediate the degradation of extracellular particles from endocytosis and of intracellular components from autophagy. The digested products are transported out of the lysosome via specific catabolite exporters or via vesicular membrane trafficking. Lysosomes also contain more than 50 membrane proteins and are equipped with the machinery to sense nutrient availability, which determines the distribution, number, size, and activity of lysosomes to control the specificity of cargo flux and timing (the initiation and termination) of degradation. Defects in degradation, export, or trafficking result in lysosomal dysfunction and lysosomal storage diseases (LSDs). Lysosomal channels and transporters mediate ion flux across perimeter membranes to regulate lysosomal ion homeostasis, membrane potential, catabolite export, membrane trafficking, and nutrient sensing. Dysregulation of lysosomal channels underlies the pathogenesis of many LSDs and possibly that of metabolic and common neurodegenerative diseases.

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“…As cholesterol accumulation is commonly seen in many LSDs, activating TRPML1 may represent a novel therapeutic approach for many other LSDs. TRPML-specific agonists such as SF compounds (SF-51) and ML-SA1 have been successfully used for in vitro studies ( 86,110 ). They, together with the next generation TRPML-specifi c compounds, may also facilitate the in vivo investigation of TRPML1 as a therapeutic strategy for lipid storage disorders.…”

Section: Stimulating Exocytosis To Clear Lysosomal Lipid Storagementioning

confidence: 99%

Lysosomal exocytosis and lipid storage disorders

Samie

2014

Journal of Lipid Research

146

178

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respective smaller building-block molecules: amino acids, monosaccharides, free fatty acids, or nucleotides ( 1-4 ). Hence, since their discovery by Christian De Duve in 1955, lysosomes have been viewed as the cell's degradation center ( 3,5 ). Lysosomes, several hundreds of them in each mammalian cell, are heterogeneous in size (100-1,000 nm) and morphology, and collectively constitute ‫ف‬ 5% of the cell volume ( 6 ). Lysosomes are filled with more than 50 different types of hydrolases: sulphatases, phosphatases, lipases, proteases, carbohydrases, and glycosidases, which effectively catabolize proteins and complex lipids into their building-block molecules ( 1, 4 ). The functions of most lysosomal hydrolytic enzymes require an acidic lumen, which is established and maintained by the vacuolarATPase (V-ATPase)... proton pumps located on the perimeter limited membrane ( 6 ). To protect the perimeter membrane and its resident membrane proteins from degradation, the inner leafl et of the lysosomal membrane is coated with a polysaccharide layer called the glycocalyx ( 7 ).The biomaterials destined for degradation are delivered to lysosomes through endocytic/phagocytic and autophagic pathways ( Fig. 1 ). Endocytosis or phagocytosis of extracellular particles or plasma membrane proteins begins with the invagination of the plasma membrane to form endocytic vesicles, which then undergo a series of maturation processes to fi rst become early endosomes, and then late endosomes [excellently reviewed in ( 5 )] ( Fig. 1 ). In the late endosomes, the destined-to-be-degraded cargo is sorted into the intraluminal vesicles via the endosomal sorting complexes required for transport system ( 5 ). Intraluminal Abstract Lysosomes are acidic compartments in mammalian cells that are primarily responsible for the breakdown of endocytic and autophagic substrates such as membranes, proteins, and lipids into their basic building blocks. Lysosomal storage diseases (LSDs) are a group of metabolic disorders caused by genetic mutations in lysosomal hydrolases required for catabolic degradation, mutations in lysosomal membrane proteins important for catabolite export or membrane traffi cking, or mutations in nonlysosomal proteins indirectly affecting these lysosomal functions. A hallmark feature of LSDs is the primary and secondary excessive accumulation of undigested lipids in the lysosome, which causes lysosomal dysfunction and cell death, and subsequently pathological symptoms in various tissues and organs. There are more than 60 types of LSDs, but an effective therapeutic strategy is still lacking for most of them. Several recent in vitro and in vivo studies suggest that induction of lysosomal exocytosis could effectively reduce the accumulation of the storage materials. Meanwhile, the molecular machinery and regulatory mechanisms for lysosomal exocytosis are beginning to be revealed. In this paper, we fi rst discuss these recent developments with the focus on the functional interactions between lipid storage and lysosomal exocytosis. We th...

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Role of TRPML and Two-Pore Channels in Endolysosomal Cation Homeostasis

Cited by 74 publications

References 90 publications

Constitutive Activity of TRPML2 and TRPML3 Channels versus Activation by Low Extracellular Sodium and Small Molecules

Constitutive Activity of TRPML2 and TRPML3 Channels versus Activation by Low Extracellular Sodium and Small Molecules

Lysosomal Physiology

Lysosomal exocytosis and lipid storage disorders

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