scholarly journals Small-molecule activation of lysosomal TRP channels ameliorates Duchenne muscular dystrophy in mouse models

2020 ◽  
Vol 6 (6) ◽  
pp. eaaz2736 ◽  
Author(s):  
Lu Yu ◽  
Xiaoli Zhang ◽  
Yexin Yang ◽  
Dan Li ◽  
Kaiyuan Tang ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Elevated Serum ◽  
Receptor Potential ◽  
Small Molecule Activation ◽  
Activation Of Transcription ◽  
Transient Receptor

Duchenne muscular dystrophy (DMD) is a devastating disease caused by mutations in dystrophin that compromise sarcolemma integrity. Currently, there is no treatment for DMD. Mutations in transient receptor potential mucolipin 1 (ML1), a lysosomal Ca2+ channel required for lysosomal exocytosis, produce a DMD-like phenotype. Here, we show that transgenic overexpression or pharmacological activation of ML1 in vivo facilitates sarcolemma repair and alleviates the dystrophic phenotypes in both skeletal and cardiac muscles of mdx mice (a mouse model of DMD). Hallmark dystrophic features of DMD, including myofiber necrosis, central nucleation, fibrosis, elevated serum creatine kinase levels, reduced muscle force, impaired motor ability, and dilated cardiomyopathies, were all ameliorated by increasing ML1 activity. ML1-dependent activation of transcription factor EB (TFEB) corrects lysosomal insufficiency to diminish muscle damage. Hence, targeting lysosomal Ca2+ channels may represent a promising approach to treat DMD and related muscle diseases.

scholarly journals Epithelial transient receptor potential ankyrin 1 (TRPA1)-dependent adrenomedullin upregulates blood flow in rat small intestine

2013 ◽  
Vol 304 (4) ◽  
pp. G428-G436 ◽  
Author(s):  
Toru Kono ◽  
Atsushi Kaneko ◽  
Yuji Omiya ◽  
Katsuya Ohbuchi ◽  
Nagisa Ohno ◽  
...  
Keyword(s):  
Blood Flow ◽  
Small Intestine ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Allyl Isothiocyanate ◽  
Antibody Treatment ◽  
Functional Roles ◽  
Transient Receptor

The functional roles of transient receptor potential (TRP) channels in the gastrointestinal tract have garnered considerable attention in recent years. We previously reported that daikenchuto (TU-100), a traditional Japanese herbal medicine, increased intestinal blood flow (IBF) via adrenomedullin (ADM) release from intestinal epithelial (IE) cells (Kono T et al. J Crohns Colitis 4: 161–170, 2010). TU-100 contains multiple TRP activators. In the present study, therefore, we examined the involvement of TRP channels in the ADM-mediated vasodilatatory effect of TU-100. Rats were treated intraduodenally with the TRP vanilloid type 1 (TRPV1) agonist capsaicin (CAP), the TRP ankyrin 1 (TRPA1) agonist allyl-isothiocyanate (AITC), or TU-100, and jejunum IBF was evaluated using laser-Doppler blood flowmetry. All three compounds resulted in vasodilatation, and the vasodilatory effect of TU-100 was abolished by a TRPA1 antagonist but not by a TRPV1 antagonist. Vasodilatation induced by AITC and TU-100 was abrogated by anti-ADM antibody treatment. RT-PCR and flow cytometry revealed that an IEC-6 cell line originated from the small intestine and purified IE cells expressed ADM and TRPA1 but not TRPV1. AITC increased ADM release in IEC cells remarkably, while CAP had no effect. TU-100 and its ingredient 6-shogaol (6SG) increased ADM release dose-dependently, and the effects were abrogated by a TRPA1 antagonist. 6SG showed similar TRPA1-dependent vasodilatation in vivo. These results indicate that TRPA1 in IE cells may play an important role in controlling bowel microcirculation via ADM release. Epithelial TRPA1 appears to be a promising target for the development of novel strategies for the treatment of various gastrointestinal disorders.

scholarly journals Transient receptor potential channel 6 regulates abnormal cardiac S-nitrosylation in Duchenne muscular dystrophy

2017 ◽  
Vol 114 (50) ◽  
pp. E10763-E10771 ◽  
Author(s):  
Heaseung Sophia Chung ◽  
Grace E. Kim ◽  
Ronald J. Holewinski ◽  
Vidya Venkatraman ◽  
Guangshuo Zhu ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Muscle Disease ◽  
Intracellular Ca ◽  
Transient Receptor ◽  
The Impact

Duchenne muscular dystrophy (DMD) is an X-linked disorder with dystrophin loss that results in skeletal and cardiac muscle weakening and early death. Loss of the dystrophin–sarcoglycan complex delocalizes nitric oxide synthase (NOS) to alter its signaling, and augments mechanosensitive intracellular Ca2+ influx. The latter has been coupled to hyperactivation of the nonselective cation channel, transient receptor potential canonical channel 6 (Trpc6), in isolated myocytes. As Ca2+ also activates NOS, we hypothesized that Trpc6 would help to mediate nitric oxide (NO) dysregulation and that this would be manifest in increased myocardial S-nitrosylation, a posttranslational modification increasingly implicated in neurodegenerative, inflammatory, and muscle disease. Using a recently developed dual-labeling proteomic strategy, we identified 1,276 S-nitrosylated cysteine residues [S-nitrosothiol (SNO)] on 491 proteins in resting hearts from a mouse model of DMD (dmdmdx:utrn+/−). These largely consisted of mitochondrial proteins, metabolic regulators, and sarcomeric proteins, with 80% of them also modified in wild type (WT). S-nitrosylation levels, however, were increased in DMD. Genetic deletion of Trpc6 in this model (dmdmdx:utrn+/−:trpc6−/−) reversed ∼70% of these changes. Trpc6 deletion also ameliorated left ventricular dilation, improved cardiac function, and tended to reduce fibrosis. Furthermore, under catecholamine stimulation, which also increases NO synthesis and intracellular Ca2+ along with cardiac workload, the hypernitrosylated state remained as it did at baseline. However, the impact of Trpc6 deletion on the SNO proteome became less marked. These findings reveal a role for Trpc6-mediated hypernitrosylation in dmdmdx:utrn+/− mice and support accumulating evidence that implicates nitrosative stress in cardiac and muscle disease.

Abstract 250: Canonical Transient Receptor Potential Channel 6 Ameliorates Increased Cardiac S-nitrosylation in Duchenne Muscular Dystrophy

2017 ◽  
Vol 121 (suppl_1) ◽  
Author(s):  
Grace E Kim ◽  
Heaseung S Chung ◽  
Ronald J Holewinski ◽  
Guangshuo Zhu ◽  
Vidya Venkatraman ◽  
...  
Keyword(s):  
Duchenne Muscular Dystrophy ◽  
Muscular Dystrophy ◽  
Transient Receptor Potential ◽  
Nitrosative Stress ◽  
Mechanical Load ◽  
Gene Activation ◽  
Receptor Potential ◽  
Left Ventricular ◽  
Tissue Growth ◽  
Transient Receptor

Duchenne muscular dystrophy (DMD) is an X-linked disorder that markedly weakens skeletal and cardiac muscle to cause early death. Its elimination of dystrophin disrupts nitric oxide (NO) signaling and amplifies intracellular Ca 2+ responses to mechanical load. We have shown the latter is linked to hyperstimulated transient receptor potential canonical 6 (TRPC6) cation channels. As Ca 2+ also activates NO synthase, we hypothesized TRPC6 couples to redox-dependent nitrosative stress to broadly impact protein S-nitrosylation (SNO). Using an unbiased, dual-labeling proteomic strategy we identified 1276 SNO sites on 491 proteins in DMD hearts (dystrophin/utrophin +/- ), of which 102 sites among 69 proteins were unique to DMD. Many of the targeted proteins were mitochondrial or metabolic regulators and sarcomere proteins - including titin, myosin binding protein-C, α-myosin heavy-chain, and tropomyosin α1 - that were hyper-nitrosylated. A key redox regulator peroxiredoxin1 was also hyper-nitrosylated at Cys173, a site previously shown to be a requisite regulator of its dimerization and enzymatic activity. DMD mice were then crossed into a Trpc6 -/- background, and proteomic analysis now found 70% of SNO targeted residues in DMD were reversed towards normal (p<0.01, χ 2 ). Trpc6 deletion improved left ventricular dilation (13.7±1.2mm, 22.4±3.9mm, 15.3±2.3mm; p<0.01), fractional shortening (58.5±0.5%, 50.3±1.0%, 59.6±1.2%, p<0.001), and fibrosis (2.3±0.9%, 6.2±0.9%, 3.7±0.6%; p<0.0001) in WT, DMD and DMD-TRPC6 -/- respectively (1-way ANOVA), and reversed pro-fibrotic gene activation (connective tissue growth factor, fibronectin1 and osteopontin). These results provide the first broad-based SNO analysis of the DMD heart, and support linkage between abnormal calcium via TRPC6, nitrosative stress and cardiac disease.

scholarly journals Transient Receptor Potential Channel Expression Signatures in Tumor-Derived Endothelial Cells: Functional Roles in Prostate Cancer Angiogenesis

Cancers ◽  
2019 ◽  
Vol 11 (7) ◽  
pp. 956 ◽  
Author(s):  
Michela Bernardini ◽  
Alessia Brossa ◽  
Giorgia Chinigo ◽  
Guillaume P. Grolez ◽  
Giulia Trimaglio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Progression ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Angiogenic Factor ◽  
Renal Tumors ◽  
Transient Receptor

Background: Transient receptor potential (TRP) channels control multiple processes involved in cancer progression by modulating cell proliferation, survival, invasion and intravasation, as well as, endothelial cell (EC) biology and tumor angiogenesis. Nonetheless, a complete TRP expression signature in tumor vessels, including in prostate cancer (PCa), is still lacking. Methods: In the present study, we profiled by qPCR the expression of all TRP channels in human prostate tumor-derived ECs (TECs) in comparison with TECs from breast and renal tumors. We further functionally characterized the role of the ‘prostate-associated’ channels in proliferation, sprout formation and elongation, directed motility guiding, as well as in vitro and in vivo morphogenesis and angiogenesis. Results: We identified three ‘prostate-associated’ genes whose expression is upregulated in prostate TECs: TRPV2 as a positive modulator of TEC proliferation, TRPC3 as an endothelial PCa cell attraction factor and TRPA1 as a critical TEC angiogenic factor in vitro and in vivo. Conclusions: We provide here the full TRP signature of PCa vascularization among which three play a profound effect on EC biology. These results contribute to explain the aggressive phenotype previously observed in PTEC and provide new putative therapeutic targets.

scholarly journals Internal Ca2+ release in yeast is triggered by hypertonic shock and mediated by a TRP channel homologue

2002 ◽  
Vol 156 (1) ◽  
pp. 29-34 ◽  
Author(s):  
Valérie Denis ◽  
Martha S. Cyert
Keyword(s):  
Mammalian Cells ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Second Messengers ◽  
Receptor Potential ◽  
Ip3 Receptors ◽  
Intracellular Compartments ◽  
No Signaling ◽  
Transient Receptor

Calcium ions, present inside all eukaryotic cells, are important second messengers in the transduction of biological signals. In mammalian cells, the release of Ca2+ from intracellular compartments is required for signaling and involves the regulated opening of ryanodine and inositol-1,4,5-trisphosphate (IP3) receptors. However, in budding yeast, no signaling pathway has been shown to involve Ca2+ release from internal stores, and no homologues of ryanodine or IP3 receptors exist in the genome. Here we show that hyperosmotic shock provokes a transient increase in cytosolic Ca2+ in vivo. Vacuolar Ca2+, which is the major intracellular Ca2+ store in yeast, is required for this response, whereas extracellular Ca2+ is not. We aimed to identify the channel responsible for this regulated vacuolar Ca2+ release. Here we report that Yvc1p, a vacuolar membrane protein with homology to transient receptor potential (TRP) channels, mediates the hyperosmolarity induced Ca2+ release. After this release, low cytosolic Ca2+ is restored and vacuolar Ca2+ is replenished through the activity of Vcx1p, a Ca2+/H+ exchanger. These studies reveal a novel mechanism of internal Ca2+ release and establish a new function for TRP channels.

scholarly journals A capsaicinoid-based soft drug, AG1529, for attenuating TRPV1-mediated histaminergic and inflammatory sensory neuron excitability

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Magdalena Nikolaeva-Koleva ◽  
Laura Butron ◽  
Sara González-Rodríguez ◽  
Isabel Devesa ◽  
Pierluigi Valente ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Primary Cultures ◽  
Receptor Potential ◽  
Neuronal Firing ◽  
In Vivo Model ◽  
Drg Neurons ◽  
Trpv1 Channels ◽  
Soft Drug ◽  
Transient Receptor

AbstractTRPV1, a member of the transient receptor potential (TRP) family, is a nonselective calcium permeable ion channel gated by physical and chemical stimuli. In the skin, TRPV1 plays an important role in neurogenic inflammation, pain and pruritus associated to many dermatological diseases. Consequently, TRPV1 modulators could represent pharmacological tools to respond to important patient needs that still represent an unmet medical demand. Previously, we reported the design of capsaicinoid-based molecules that undergo dermal deactivation (soft drugs), thus preventing their long-term dermal accumulation. Here, we investigated the pharmacological properties of the lead antagonist, 2-((4-hydroxy-2-iodo-5-methoxybenzyl) amino)-2-oxoethyl dodecanoate (AG1529), on heterologously expressed human TRPV1 (hTRPV1), on nociceptor excitability and on an in vivo model of acute pruritus. We report that AG1529 competitively blocked capsaicin-evoked activation of hTRPV1 with micromolar potency, moderately affected pH-induced gating, and did not alter voltage- and heat-mediated responses. AG1529 displays modest receptor selectivity as it mildly blocked recombinant hTRPA1 and hTRPM8 channels. In primary cultures of rat dorsal root ganglion (DRG) neurons, AG1529 potently reduced capsaicin-evoked neuronal firing. AG1529 exhibited lower potency on pH-evoked TRPV1 firing, and TRPA1-elicited nociceptor excitability. Furthermore, AG1529 abolished histaminergic and inflammation mediated TRPV1 sensitization in primary cultures of DRG neurons. Noteworthy, dermal wiping of AG1529, either in an acetone-based formulation or in an anhydrous ointment, dose-dependently attenuated acute histaminergic itch in a rodent model. This cutaneous anti-pruritic effect was devoid of the normal nocifensive action evoked by the burning sensation of capsaicin. Taken together, these preclinical results unveil the mode of action of AG1529 on TRPV1 channels and substantiate the tenet that this capsaicinoid-based soft drug is a promising candidate for drug development as a topical anti-pruritic and anti-inflammatory medication.

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