Lysosomal Ion Channels: What Are They Good For and Are They Druggable Targets?

The Annual Review of Pharmacology and Toxicology, Год журнала: 2022, Номер 63(1), С. 19 - 41

Опубликована: Сен. 24, 2022

Lysosomes play fundamental roles in material digestion, cellular clearance, recycling, exocytosis, wound repair, Ca2+ signaling, nutrient and gene expression regulation. The organelle also serves as a hub for important signaling networks involving the mTOR AKT kinases. Electrophysiological recording molecular structural studies past decade have uncovered several unique lysosomal ion channels transporters, including TPCs, TMEM175, TRPMLs, CLN7, CLC-7. They underlie organelle's permeability to major ions, K+, Na+, H+, Ca2+, Cl-. are regulated by numerous factors, ranging from H+ lumen voltage across membrane ATP cytosol growth factors outside cell. Genetic variations channel/transporter genes associated with diseases that include storage neurodegenerative diseases. Recent human genetics channel activators suggest may be attractive targets development of therapeutics prevention intervention

Язык: Английский

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Novel Insight into Functions of Transcription Factor EB (TFEB) in Alzheimer’s Disease and Parkinson’s Disease

Aging and Disease, Год журнала: 2023, Номер 14(3), С. 652 - 652

Опубликована: Янв. 1, 2023

A key pathological feature of neurodegenerative diseases (NDs) such as Alzheimer’s disease (AD) and Parkinson’s (PD) is the accumulation aggregated misfolded protein aggregates with limited effective therapeutic agents. TFEB (transcription factor EB), a regulator lysosomal biogenesis autophagy, plays pivotal role in degradation has thus been regarded promising target for these NDs. Here, we systematically summarize molecular mechanisms function regulation. We then discuss roles autophagy-lysosome pathways major including AD PD. Finally, illustrate small molecule activators protective NDs animal models, which show great potential being further developed into novel anti-neurodegenerative Overall, targeting enhancing autophagy may represent opportunity discovery disease-modifying therapeutics disorders though more in-depth basic clinical studies are required future.

Язык: Английский

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Transcriptional dysregulation of autophagy in the muscle of a mouse model of Duchenne muscular dystrophy

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 16, 2024

Abstract It has been reported that autophagic activity is disturbed in the skeletal muscles of dystrophin-deficient mdx mice and patients with Duchenne muscular dystrophy (DMD). Transcriptional regulations autophagy by FoxO transcription factors (FoxOs) factor EB (TFEB) play critical roles adaptation to cellular stress conditions. Here, we investigated whether dysregulated at level muscles. Expression levels autophagy-related genes were globally decreased tibialis anterior soleus compared those wild-type mice. DNA microarray data from NCBI database also showed related downregulated DMD. These are known as targets FoxOs TFEB. Immunostaining nuclear localization FoxO1 FoxO3a was Western blot analyses demonstrated increases phosphorylation Nuclear TFEB reduced mice, which associated elevated Collectively, results suggest via transcriptional downregulation due phosphorylation-mediated suppression

Язык: Английский

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Estradiol analogs attenuate autophagy, cell migration and invasion by direct and selective inhibition of TRPML1, independent of estrogen receptors

Scientific Reports, Год журнала: 2021, Номер 11(1)

Опубликована: Апрель 15, 2021

Abstract The cation channel TRPML1 is an important regulator of lysosomal function and autophagy. Loss associated with neurodegeneration storage disease, while temporary inhibition this ion has been proposed to be beneficial in cancer therapy. Currently available inhibitors are not TRPML isoform selective block at least two the three human isoforms. We have now identified first highly potent isoform-selective antagonist, steroid 17β-estradiol methyl ether (EDME). Two analogs EDME, PRU-10 PRU-12, characterized by their reduced activity estrogen receptor, through systematic chemical modification lead structure. EDME its analogs, besides being promising new small molecule tool compounds for investigation TRPML1, selectively affect key features function: autophagy induction transcription factor EB (TFEB) translocation. In addition, they act as triple-negative breast cell migration invasion.

Язык: Английский

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Two-pore and TRPML cation channels: Regulators of phagocytosis, autophagy and lysosomal exocytosis

Pharmacology & Therapeutics, Год журнала: 2020, Номер 220, С. 107713 - 107713

Опубликована: Окт. 24, 2020

Язык: Английский

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Transient Receptor Potential channels (TRP) in GtoPdb v.2023.2

IUPHAR/BPS Guide to Pharmacology CITE, Год журнала: 2023, Номер 2023(2)

Опубликована: Авг. 7, 2023

The TRP superfamily of channels (nomenclature as agreed by NC-IUPHAR [176, 1072]), whose founder member is the Drosophila Trp channel, exists in mammals six families; TRPC, TRPM, TRPV, TRPA, TRPP and TRPML based on amino acid homologies. subunits contain putative TM domains assemble homo- or hetero-tetramers to form cation selective with diverse modes activation varied permeation properties (reviewed [730]). Established, potential, physiological functions individual members families are discussed detail recommended reviews a number books [401, 686, 1155, 256]. established, involvement disease [1126] reviewed [448, 685], [688] [464], together special edition Biochemica et Biophysica Acta subject [685]. Additional related reviews, for pain [633], stroke [1135], sensation inflammation [988], itch [130], airway [310, 1051], available. pharmacology most has been advanced recent years. Broad spectrum agents listed tables along more selective, recently recognised, ligands that flagged inclusion primary reference. See Rubaiy (2019) review pharmacological tools TRPC1/C4/C5 [805]. Most regulated phosphoinostides such PtIns(4,5)P2 although effects reported often complex, occasionally contradictory, likely be dependent upon experimental conditions, intracellular ATP levels [1009, 689, 801]). Such regulation generally not included tables.When thermosensitivity mentioned, it refers specifically high Q10 gating, range 10-30, but does necessarily imply channel's function act 'hot' 'cold' sensor. In general, search activators led many claims temperature sensing, mechanosensation, lipid sensing. All proteins course sensitive energies binding, mechanical force, temperature, issue whether proposed input within physiologically relevant resulting response. TRPA (ankyrin) familyTRPA1 sole mammalian this group [293]). TRPA1 sensory neurons contribute nociception [414, 890, 602]. Pungent chemicals mustard oil (AITC), allicin, cinnamaldehyde activate modification free thiol groups cysteine side chains, especially those located its terminus [575, 60, 365, 577]. Alkenals α, β-unsaturated bonds, propenal (acrolein), butenal (crotylaldehyde), 2-pentenal can react thiols via Michael addition TRPA1. However, potency appears weaken carbon chain length increases [26, 60]. Covalent leads sustained Chemicals including carvacrol, menthol, local anesthetics reversibly non-covalent binding [424, 511, 1081, 1080]. mechanosensitive under activated cold temperatures [425, 212]. electron cryo-EM structure [740] indicates 6-TM homotetramer. Each subunit channel contains two short ‘pore helices’ pointing into ion selectivity filter, which big enough allow partially hydrated Ca2+ ions. TRPC (canonical) familyMembers subfamily [284, 778, 18, 4, 94, 446, 739, 70]) fall subgroups outlined below. TRPC2 pseudogene humans. It accepted all downstream Gq/11-coupled receptors, receptor tyrosine kinases [765, 953, 1072]). A comprehensive listing G-protein coupled receptors given [4]. Hetero-oligomeric complexes their association signalling detailed [18] [447]. have frequently store-operated (SOCs) (or compenents mulimeric SOCs), depletion calcium stores [741, 770, 820, 1121, 157, 726, 64, 158]). weight evidence they directly gated conventional mechanisms, established Stim-gated Orai channels. mechanically ranges force. family blocked 2-APB SKF96365 [347, 346]. Activation lipids [70]. Important progress made [805, 619, 436, 102, 851, 191, 291]. regulate variety implicated human diseases [295, 71, 885, 1031, 1025, 154, 103, 561, 913, 409]. subgroup TRPC1 alone may functional [229]. TRPC4/C5 distinguished from other potentiation micromolar concentrations La3+. humans, an localized microvilli vomeronasal organ. required normal sexual behavior response pheromones mice. also main olfactory epithelia mice [1114, 723, 724, 1115, 539, 1168, 1109].TRPC3/C6/C7 diacylglycerol independent protein kinase C stimulation [347].TRPM (melastatin) TRPM [275, 346, 741, 1151]) five TRPM1/M3 subgroupIn darkness, glutamate released photoreceptors ON-bipolar cells binds metabotropic 6 , leading Go . This results closure TRPM1. When stimulated light, release reduced, TRPM1 active, cell membrane depolarization. Human mutations associated congenital stationary night blindness (CSNB), patients lack rod function. found melanocytes. Isoforms present melanocytes, melanoma, brain, retina. melanoma cells, prevalent highly dynamic vesicular structures [398, 708]. TRPM3 [714]) multiple splice variants differ significantly biophysical properties. expressed somatosensory important development heat hyperalgesia during (see [941]). coexpressed TRPV1 these neurons. pancreatic beta well pituitary gland, eye, kidney, adipose tissue [713, 940]. detection noxious [1017]. TRPM2TRPM2 conditions oxidative stress (respiratory burst phagocytic cells). direct calcium, adenosine diphosphate ribose (ADPR) [970] cyclic ADPR (cADPR) [1118]. As channels, PI(4,5)P2 must [1109]. Numerous TRPM2 exist mechanisms [239]. Recent studies (hs) TRPM2, demonstrate sites hsTRPM2, one N-terminal MHR1/2 domain C-terminal NUDT9-H domain. addition, site S2-S3 loop revealed mediate induces conformational changes ADPR-bound closed open [387, 1027]. Meanwhile, quadruple-residue motif (979FGQI982) was identified filter gate control hsTRPM2 [1120]. involved warmth [848], contributes several [76]. interacts extra synaptic NMDA (NMDAR) enhances NMDAR activity ischemic [1164]. macrophages promotes atherosclerosis [1165, 1147]. Moreover, silica nanoparticles induce lung ROS/PARP/TRPM2 signaling-mediated lysosome impairment autophagy dysfunction [1028]. designed various compounds potential selectively inhibit ACA derivatives A23, 2,3-dihydroquinazolin-4(1H)-one [1137, 1139]. TRPM4/5 subgroupTRPM4 TRPM5 distinction being impermeable [1072]. variant TRPM4 (i.e.TRPM4b) molecular candidates endogenous calcium-activated (CAN) [327]. active late phase repolarization cardiac ventricular action potential. deletion knockout adrenergic-mediated inotropy [593]. Mutations conduction defects [404, 593, 879]. shown regulator entry mast [993] dendritic migration [52]. taste tongue essential transduction sweet, bitter stimuli [537] slow afterdepolarization layer 5 mouse prefrontal cortex [513]. Both [246]. TRPM6/7 subgroupTRPM6 7 combine enzymatic activities (‘chanzymes’) [172]. These unusual property divalent (Ca2+, Mg2+, Zn2+) monovalent cations, single conductances, overall extremely small inward conductance when plasma membrane. They inhibited internal Mg2+ at ~0.6 mM, around level cells. Whether homeostasis contentious issue. PIP2 TRPM6 TRPM7 [810, 1077]. either gene deleted mice, result embryonic lethality [413, 1065]. region cleaved unknown stimuli, phosphorylates nuclear histones [479, 480]. responsible oxidant- induced Zn2+ vesicles [3] intestinal mineral absorption postnatal survival [622]. metal transporter CNNM1-4 interact [40, 467]. TRPM8Is cooling evoking ‘cool’ participates thermosensation [63, 178, 224] [1011, 562, 457, 649]. Direct chemical agonists include menthol icilin[1086]. Besides, linalool promote ERK phosphorylation dermal microvascular endothelial down-regulate levels, TRPM8 [68]. typical S4-S5 connectomes clear filters exowell rings [512], cryo-electron microscopy closed, intermediate, states ligand- PIP2-dependent pathways [1111]. last 36 acids carboxyl terminal key sequences TRPM8's temperature-sensitive [194]. deficiency reduced expression S100A9 increased HNF4α liver fibrosis progression fibrosis, helped alleviate symptoms bile duct [556]. Channel shortens time hypersensitivity reactions migraine models promoting recovery sensitivity [12]. peptide DeC‐1.2 ligand activation, eliminate dysalgesia oxaliplatin-treated without changing body [9]. Analysis clinical data shows TRPM8-specific blockers WS12 reduce tumor growth colorectal cancer xenografted reducing transcription Wnt signaling regulators β-catenin target oncogenes, C-Myc Cyclin D1 [732]. (mucolipin) familyThe [782, 1132, 775, 1084, 190] consists three (TRPML1-3). probably restricted (MCOLN1) encoding TRPML1 (mucolipin-1) cause neurodegenerative disorder mucolipidosis type IV (MLIV) man. sorting/transport endosomes endocytotic pathway specifically, fission endosome-lysosome hybrid lysosomal exocytosis [822]. TRPML2 TRPML3 show low luminal sodium and/or pH, similar molecules [319, 147, 877]. naturally occurring gain mutation (i.e. A419P) varitint waddler (Va) phenotype 690]). (polycystin) [216, 214, 300, 1061, 374]) PKD2 comprised (PC2), PKD2L1 (PC2L1), PKD2L2 (PC2L2), renamed TRPP1, TRPP2 TRPP3, respectively should noted nomenclature PC2 old literature. uniformed called [345]. clearly distinct PKD1 family, unknown. hetero-oligomeric complex 1:3 ratio. [905]. Although still sorted out, appear 6TM spanning nonselective TRPV (vanilloid) [995]) broadly divided non-selective TRPV1-4 TRPV5 TRPV6. TRPV1-V4 subfamilyTRPV1 thermal following noxius [762, 882, 922]). described, some modulate TRPV1, dominant negative manner co-expressed [844]. [329] [1015]. TRPV2 thermosensor man [736], innate immunity [547]. Functional described placental trophoblast [204]. TRPV3 TRPV4 both thermosensitive. There mechanosensitive, native environment [127, 530]. TRPV5/V6 TRPV6 placenta, bone, kidney. Under reabsorption across kidney tubule [1057, 205, 651, 270]).TRPV6 play role transport placenta [1056].

Язык: Английский

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Ca²⁺-sensor ALG-2 engages ESCRTs to enhance lysosomal membrane resilience to osmotic stress

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Фев. 5, 2024

ABSTRACT Lysosomes are central players in cellular catabolism, signaling, and metabolic regulation. Cellular environmental stresses that damage lysosomal membranes can compromise their function release toxic content into the cytoplasm. Here, we examine how cells respond to osmotic stress within lysosomes. Using sensitive assays of leakage rupture, acute effects cathepsin C-metabolized disruptant glycyl-L-phenylalanine 2-naphthylamide (GPN). Our findings reveal widely used concentrations GPN rupture only a small fraction lysosomes, but surprisingly trigger Ca 2+ from nearly all. Chelating cytoplasmic using BAPTA makes lysosomes more likely under GPN-induced stress, suggesting plays role protecting or rapidly repairing membranes. Mechanistically, establish causes -sensitive protein Apoptosis Linked Gene-2 (ALG-2) interacting ESCRT proteins redistribute onto improving resistance membrane created by as well lysosomotropic drug chlorpromazine. Furthermore, show activating cation channel TRPML1, with without blocking endoplasmic reticulum pump, creates local signals protect recruiting ALG-2 ESCRTs any damage. These , through ALG-2, helps bring enhance resilience maintain organelle integrity face stress. SIGNIFICANCE As degradative hub cell, full spill There has been much recent interest sense repair cholesterol fix “nanoscale damage”. extend understanding contribute uncovering preventative machinery. We ESCRTs, when recruited -sensor play critical stabilizing against osmotically-induced rupture. This finding suggests have mechanisms not just for also actively stress-induced

Язык: Английский

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Long-Term Protective Effect of Human Dystrophin Expressing Chimeric (DEC) Cell Therapy on Amelioration of Function of Cardiac, Respiratory and Skeletal Muscles in Duchenne Muscular Dystrophy

Stem Cell Reviews and Reports, Год журнала: 2022, Номер 18(8), С. 2872 - 2892

Опубликована: Май 19, 2022

Duchenne Muscular Dystrophy (DMD) is a lethal disease caused by mutations in dystrophin encoding gene, causing progressive degeneration of cardiac, respiratory, and skeletal muscles leading to premature death due cardiac respiratory failure. Currently, there no cure for DMD. Therefore, novel therapeutic approaches are needed DMD patients.We have previously reported functional improvements which correlated with increased expression following administration expressing chimeric (DEC) cells myoblast origin the mdx mouse models DMD.In current study, we confirmed dose-dependent protective effect human DEC therapy created from myoblasts normal DMD-affected donors, on restoration amelioration muscle function at 180 days after systemic-intraosseous mdx/scid model Functional included maintenance ejection fraction fractional shortening levels echocardiography, reduced enhanced pause expiration time plethysmography improved grip strength maximum stretch induced contraction muscles. Improved was associated pathology revealed fibrosis, inflammation morphology number centrally nucleated fibers normalization fiber diameters. Our findings confirm long-term systemic most severely affected organs including heart, diaphragm, long muscles.These encouraging preclinical data introduces as modality Advanced Therapy Medicinal Product (ATMP) potential improve or halt progression enhance quality life patients. Human Graphical abstract represents manufacturing process future clinical applications. 1. We report efficacy resulting Dystrophin Expressing Chimeric Cells 2. Systemic resulted standard tests respectively. 3. introduce application

Язык: Английский

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TRPML1 activation ameliorates lysosomal phenotypes in CLN3 deficient retinal pigment epithelial cells

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Июль 29, 2024

Mutations in the lysosomal membrane protein CLN3 cause Juvenile Neuronal Ceroid Lipofuscinosis (JNCL). Activation of ion channel TRPML1 has previously been shown to be beneficial several neurodegenerative disease models. Here, we tested whether activation rescues disease-associated phenotypes CLN3-deficient retinal pigment epithelial (ARPE-19 CLN3-KO) cells. ARPE-19 CLN3-KO cells accumulate LAMP1 positive organelles and show storage mitochondrial ATPase subunit C (SubC), globotriaosylceramide (Gb3), glycerophosphodiesters (GPDs), whereas bis(monoacylglycero)phosphate (BMP/LBPA) lipid levels were significantly decreased. reduced Gb3 SubC but failed restore BMP TRPML1-mediated decrease was TFEB-independent, identified enhanced exocytosis as a likely mechanism for clearing including GPDs. Therefore, represent human cell model showing many described core deficits, some which can improved using agonists.

Язык: Английский

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Human Dystrophin Expressing Chimeric (DEC) Cell Therapy Ameliorates Cardiac, Respiratory, and Skeletal Muscle's Function in Duchenne Muscular Dystrophy

Stem Cells Translational Medicine, Год журнала: 2021, Номер 10(10), С. 1406 - 1418

Опубликована: Июль 22, 2021

Abstract Duchenne muscular dystrophy (DMD) is a progressive and lethal disease, caused by X-linked mutations of the dystrophin encoding gene. The lack leads to muscle weakness, degeneration, fibrosis, loss skeletal, cardiac, respiratory function resulting in premature death due cardiac failure. There no cure for DMD current therapies neither nor arrest disease progression. Thus, there an urgent need develop new approaches safer patients. We have previously reported functional improvements which correlated with increased expression following transplantation expressing chimeric (DEC) cells myoblast origin mdx mouse models DMD. In this study, we demonstrated that systemic-intraosseous DEC human derived from myoblasts normal DMD-affected donors, respiratory, skeletal muscles mdx/scid model transplant preservation ejection fraction fractional shortening on echocardiography, improved plethysmography, strength limb muscles. Enhanced was associated histopathology, revealing reduced pathology, decreased inflammation, preserved morphology architecture. Our findings confirm DECs generate systemic protective effect target organs. Therefore, represents novel therapeutic approach potential preserve or enhance multiorgan critical well-being

Язык: Английский

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