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Results: 1 to 10 of 126

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Preface.
Levitan I, Delpire E
(2018) Curr Top Membr 81: xv-xvii
MeSH Terms: Animals, Cell Size, Fishes, Humans, Ion Channels, Nervous System
Added April 2, 2019
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MeSH Terms
Structure-function analyses of the ion channel TRPC3 reveal that its cytoplasmic domain allosterically modulates channel gating.
Sierra-Valdez F, Azumaya CM, Romero LO, Nakagawa T, Cordero-Morales JF
(2018) J Biol Chem 293: 16102-16114
MeSH Terms: Allosteric Regulation, Ankyrin Repeat, HEK293 Cells, Humans, Ion Channel Gating, Mutation, Protein Conformation, alpha-Helical, Protein Domains, TRPC Cation Channels
Show Abstract · Added April 10, 2019
The transient receptor potential ion channels support Ca permeation in many organs, including the heart, brain, and kidney. Genetic mutations in transient receptor potential cation channel subfamily C member 3 (TRPC3) are associated with neurodegenerative diseases, memory loss, and hypertension. To better understand the conformational changes that regulate TRPC3 function, we solved the cryo-EM structures for the full-length human TRPC3 and its cytoplasmic domain (CPD) in the apo state at 5.8- and 4.0-Å resolution, respectively. These structures revealed that the TRPC3 transmembrane domain resembles those of other TRP channels and that the CPD is a stable module involved in channel assembly and gating. We observed the presence of a C-terminal domain swap at the center of the CPD where horizontal helices (HHs) transition into a coiled-coil bundle. Comparison of TRPC3 structures revealed that the HHs can reside in two distinct positions. Electrophysiological analyses disclosed that shortening the length of the C-terminal loop connecting the HH with the TRP helices increases TRPC3 activity and that elongating the length of the loop has the opposite effect. Our findings indicate that the C-terminal loop affects channel gating by altering the allosteric coupling between the cytoplasmic and transmembrane domains. We propose that molecules that target the HH may represent a promising strategy for controlling TRPC3-associated neurological disorders and hypertension.
© 2018 Sierra-Valdez et al.
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9 MeSH Terms
Mechanosensitive Ion Channels: TRPV4 and P2X7 in Disseminating Cancer Cells.
Hope JM, Greenlee JD, King MR
(2018) Cancer J 24: 84-92
MeSH Terms: Animals, Cell Movement, Humans, Mechanotransduction, Cellular, Neoplasms, Receptors, Purinergic P2X7, TRPV Cation Channels
Show Abstract · Added April 15, 2019
Cancer metastasis is the second leading cause of death in the United States. Despite its morbidity, metastasis is an inefficient process that few cells can survive. However, cancer cells can overcome these metastatic barriers via cellular responses to microenvironmental cues, such as through mechanotransduction. This review focuses on the mechanosensitive ion channels TRPV4 and P2X7, and their roles in metastasis, as both channels have been shown to significantly affect tumor cell dissemination. Upon activation, these channels help form tumor neovasculature, promote transendothelial migration, and increase cell motility. Conversely, they have also been linked to forms of cancer cell death dependent upon levels of activation, implying the complex functionality of mechanosensitive ion channels. Understanding the roles of TRPV4, P2X7 and other mechanosensitive ion channels in these processes may reveal new possible drug targets that modify channel function to reduce a tumor's metastatic potential.
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Inhibition of WNT signaling attenuates self-renewal of SHH-subgroup medulloblastoma.
Rodriguez-Blanco J, Pednekar L, Penas C, Li B, Martin V, Long J, Lee E, Weiss WA, Rodriguez C, Mehrdad N, Nguyen DM, Ayad NG, Rai P, Capobianco AJ, Robbins DJ
(2017) Oncogene 36: 6306-6314
MeSH Terms: Anilides, Animals, Cell Line, Tumor, Cerebellar Neoplasms, Disease Models, Animal, HEK293 Cells, Hedgehog Proteins, Humans, Male, Medulloblastoma, Mice, Mice, Transgenic, Pyridines, Random Allocation, SOXB1 Transcription Factors, Small Molecule Libraries, TRPC Cation Channels, Transfection, Tumor Suppressor Protein p53, Veratrum Alkaloids, Wnt Proteins, Wnt Signaling Pathway
Show Abstract · Added July 18, 2017
The SMOOTHENED inhibitor vismodegib is FDA approved for advanced basal cell carcinoma (BCC), and shows promise in clinical trials for SONIC HEDGEHOG (SHH)-subgroup medulloblastoma (MB) patients. Clinical experience with BCC patients shows that continuous exposure to vismodegib is necessary to prevent tumor recurrence, suggesting the existence of a vismodegib-resistant reservoir of tumor-propagating cells. We isolated such tumor-propagating cells from a mouse model of SHH-subgroup MB and grew them as sphere cultures. These cultures were enriched for the MB progenitor marker SOX2 and formed tumors in vivo. Moreover, while their ability to self-renew was resistant to SHH inhibitors, as has been previously suggested, this self-renewal was instead WNT-dependent. We show here that loss of Trp53 activates canonical WNT signaling in these SOX2-enriched cultures. Importantly, a small molecule WNT inhibitor was able to reduce the propagation and growth of SHH-subgroup MB in vivo, in an on-target manner, leading to increased survival. Our results imply that the tumor-propagating cells driving the growth of bulk SHH-dependent MB are themselves WNT dependent. Further, our data suggest combination therapy with WNT and SHH inhibitors as a therapeutic strategy in patients with SHH-subgroup MB, in order to decrease the tumor recurrence commonly observed in patients treated with vismodegib.
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22 MeSH Terms
TRPM2 ion channels regulate macrophage polarization and gastric inflammation during Helicobacter pylori infection.
Beceiro S, Radin JN, Chatuvedi R, Piazuelo MB, Horvarth DJ, Cortado H, Gu Y, Dixon B, Gu C, Lange I, Koomoa DL, Wilson KT, Algood HM, Partida-Sánchez S
(2017) Mucosal Immunol 10: 493-507
MeSH Terms: Animals, Calcium Signaling, Cell Differentiation, Cells, Cultured, Cytokines, Gastritis, Helicobacter Infections, Helicobacter pylori, Inflammation Mediators, Macrophage Activation, Macrophages, Mice, Mice, Inbred C57BL, Mice, Knockout, NADP, Oxidative Stress, Reactive Oxygen Species, TRPM Cation Channels
Show Abstract · Added July 30, 2016
Calcium signaling in phagocytes is essential for cellular activation, migration, and the potential resolution of infection or inflammation. The generation of reactive oxygen species (ROS) via activation of NADPH (nicotinamide adenine dinucleotide phosphate)-oxidase activity in macrophages has been linked to altered intracellular calcium concentrations. Because of its role as an oxidative stress sensor in phagocytes, we investigated the function of the cation channel transient receptor potential melastatin 2 (TRPM2) in macrophages during oxidative stress responses induced by Helicobacter pylori infection. We show that Trpm2/ mice, when chronically infected with H. pylori, exhibit increased gastric inflammation and decreased bacterial colonization compared with wild-type (WT) mice. The absence of TRPM2 triggers greater macrophage production of inflammatory mediators and promotes classically activated macrophage M1 polarization in response to H. pylori. TRPM2-deficient macrophages upon H. pylori stimulation are unable to control intracellular calcium levels, which results in calcium overloading. Furthermore, increased intracellular calcium in TRPM2/ macrophages enhanced mitogen-activated protein kinase and NADPH-oxidase activities, compared with WT macrophages. Our data suggest that augmented production of ROS and inflammatory cytokines with TRPM2 deletion regulates oxidative stress in macrophages and consequently decreases H. pylori gastric colonization while increasing inflammation in the gastric mucosa.
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18 MeSH Terms
The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons.
Miller-Fleming TW, Petersen SC, Manning L, Matthewman C, Gornet M, Beers A, Hori S, Mitani S, Bianchi L, Richmond J, Miller DM
(2016) Elife 5:
MeSH Terms: Animals, Caenorhabditis elegans, Caenorhabditis elegans Proteins, GABAergic Neurons, Gene Expression Regulation, Ion Channels, Neuronal Plasticity
Show Abstract · Added March 26, 2019
Genetic programming and neural activity drive synaptic remodeling in developing neural circuits, but the molecular components that link these pathways are poorly understood. Here we show that the C. elegans Degenerin/Epithelial Sodium Channel (DEG/ENaC) protein, UNC-8, is transcriptionally controlled to function as a trigger in an activity-dependent mechanism that removes synapses in remodeling GABAergic neurons. UNC-8 cation channel activity promotes disassembly of presynaptic domains in DD type GABA neurons, but not in VD class GABA neurons where unc-8 expression is blocked by the COUP/TF transcription factor, UNC-55. We propose that the depolarizing effect of UNC-8-dependent sodium import elevates intracellular calcium in a positive feedback loop involving the voltage-gated calcium channel UNC-2 and the calcium-activated phosphatase TAX-6/calcineurin to initiate a caspase-dependent mechanism that disassembles the presynaptic apparatus. Thus, UNC-8 serves as a link between genetic and activity-dependent pathways that function together to promote the elimination of GABA synapses in remodeling neurons.
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HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects.
Han Y, Heuermann RJ, Lyman KA, Fisher D, Ismail QA, Chetkovich DM
(2017) Mol Psychiatry 22: 458-465
MeSH Terms: Animals, Antidepressive Agents, CA1 Region, Hippocampal, Cyclic Nucleotide-Gated Cation Channels, Dendrites, Depressive Disorder, Major, Humans, Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels, Membrane Proteins, Mice, Mice, Knockout, Neurons, Peroxins, Potassium Channels, Protein Binding, Protein Transport
Show Abstract · Added April 2, 2019
Major depressive disorder (MDD) is a prevalent psychiatric condition with limited therapeutic options beyond monoaminergic therapies. Although effective in some individuals, many patients fail to respond adequately to existing treatments, and new pharmacologic targets are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate excitability in neurons, and blocking HCN channel function has been proposed as a novel antidepressant strategy. However, systemic blockade of HCN channels produces cardiac effects that limit this approach. Knockout (KO) of the brain-specific HCN-channel auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) also produces antidepressant-like behavioral effects and suggests that inhibiting TRIP8b function could produce antidepressant-like effects without affecting the heart. We examined the structural basis of TRIP8b-mediated HCN-channel trafficking and its relationship with antidepressant-like behavior using a viral rescue approach in TRIP8b KO mice. We found that restoring TRIP8b to the hippocampus was sufficient to reverse the impaired HCN-channel trafficking and antidepressant-like behavioral effects caused by TRIP8b KO. Moreover, we found that hippocampal expression of a mutated version of TRIP8b further impaired HCN-channel trafficking and increased the antidepressant-like behavioral phenotype of TRIP8b KO mice. Thus, modulating the TRIP8b-HCN interaction bidirectionally influences channel trafficking and antidepressant-like behavior. Overall, our work suggests that small-molecule inhibitors of the interaction between TRIP8b and HCN should produce antidepressant-like behaviors and could represent a new paradigm for the treatment of MDD.
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A Nonoligomerizing Mutant Form of Helicobacter pylori VacA Allows Structural Analysis of the p33 Domain.
González-Rivera C, Campbell AM, Rutherford SA, Pyburn TM, Foegeding NJ, Barke TL, Spiller BW, McClain MS, Ohi MD, Lacy DB, Cover TL
(2016) Infect Immun 84: 2662-70
MeSH Terms: Bacterial Proteins, Bacterial Toxins, Cell Line, Tumor, HeLa Cells, Helicobacter pylori, Humans, Ion Channels, Microscopy, Electron, Mutation, Protein Domains
Show Abstract · Added September 29, 2016
Helicobacter pylori secretes a pore-forming VacA toxin that has structural features and activities substantially different from those of other known bacterial toxins. VacA can assemble into multiple types of water-soluble flower-shaped oligomeric structures, and most VacA activities are dependent on its capacity to oligomerize. The 88-kDa secreted VacA protein can undergo limited proteolysis to yield two domains, designated p33 and p55. The p33 domain is required for membrane channel formation and intracellular toxic activities, and the p55 domain has an important role in mediating VacA binding to cells. Previous studies showed that the p55 domain has a predominantly β-helical structure, but no structural data are available for the p33 domain. We report here the purification and analysis of a nonoligomerizing mutant form of VacA secreted by H. pylori The nonoligomerizing 88-kDa mutant protein retains the capacity to enter host cells but lacks detectable toxic activity. Analysis of crystals formed by the monomeric protein reveals that the β-helical structure of the p55 domain extends into the C-terminal portion of p33. Fitting the p88 structural model into an electron microscopy map of hexamers formed by wild-type VacA (predicted to be structurally similar to VacA membrane channels) reveals that p55 and the β-helical segment of p33 localize to peripheral arms but do not occupy the central region of the hexamers. We propose that the amino-terminal portion of p33 is unstructured when VacA is in a monomeric form and that it undergoes a conformational change during oligomer assembly.
Copyright © 2016, American Society for Microbiology. All Rights Reserved.
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10 MeSH Terms
An Overview of Helicobacter pylori VacA Toxin Biology.
Foegeding NJ, Caston RR, McClain MS, Ohi MD, Cover TL
(2016) Toxins (Basel) 8:
MeSH Terms: Animals, Bacterial Proteins, Bacterial Toxins, Helicobacter pylori, Humans, Ion Channels, Protein Conformation, Transcription, Genetic
Show Abstract · Added September 29, 2016
The VacA toxin secreted by Helicobacter pylori enhances the ability of the bacteria to colonize the stomach and contributes to the pathogenesis of gastric adenocarcinoma and peptic ulcer disease. The amino acid sequence and structure of VacA are unrelated to corresponding features of other known bacterial toxins. VacA is classified as a pore-forming toxin, and many of its effects on host cells are attributed to formation of channels in intracellular sites. The most extensively studied VacA activity is its capacity to stimulate vacuole formation, but the toxin has many additional effects on host cells. Multiple cell types are susceptible to VacA, including gastric epithelial cells, parietal cells, T cells, and other types of immune cells. This review focuses on the wide range of VacA actions that are detectable in vitro, as well as actions of VacA in vivo that are relevant for H. pylori colonization of the stomach and development of gastric disease.
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8 MeSH Terms
Nerve Growth Factor Regulates Transient Receptor Potential Vanilloid 2 via Extracellular Signal-Regulated Kinase Signaling To Enhance Neurite Outgrowth in Developing Neurons.
Cohen MR, Johnson WM, Pilat JM, Kiselar J, DeFrancesco-Lisowitz A, Zigmond RE, Moiseenkova-Bell VY
(2015) Mol Cell Biol 35: 4238-52
MeSH Terms: Animals, Calcium, Calcium Channels, Cell Line, Tumor, Extracellular Signal-Regulated MAP Kinases, HEK293 Cells, Humans, MAP Kinase Signaling System, Nerve Growth Factor, Neurites, Neurogenesis, Neurons, PC12 Cells, Phosphatidylinositol 3-Kinases, Phosphorylation, RNA Interference, RNA, Small Interfering, Rats, Receptor, trkA, TRPV Cation Channels, rab GTP-Binding Proteins
Show Abstract · Added April 24, 2017
Neurite outgrowth is key to the formation of functional circuits during neuronal development. Neurotrophins, including nerve growth factor (NGF), increase neurite outgrowth in part by altering the function and expression of Ca(2+)-permeable cation channels. Here we report that transient receptor potential vanilloid 2 (TRPV2) is an intracellular Ca(2+)-permeable TRPV channel upregulated by NGF via the mitogen-activated protein kinase (MAPK) signaling pathway to augment neurite outgrowth. TRPV2 colocalized with Rab7, a late endosome protein, in addition to TrkA and activated extracellular signal-regulated kinase (ERK) in neurites, indicating that the channel is closely associated with signaling endosomes. In line with these results, we showed that TRPV2 acts as an ERK substrate and identified the motifs necessary for phosphorylation of TRPV2 by ERK. Furthermore, neurite length, TRPV2 expression, and TRPV2-mediated Ca(2+) signals were reduced by mutagenesis of these key ERK phosphorylation sites. Based on these findings, we identified a previously uncharacterized mechanism by which ERK controls TRPV2-mediated Ca(2+) signals in developing neurons and further establish TRPV2 as a critical intracellular ion channel in neuronal function.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
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21 MeSH Terms