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https://www.readbyqxmd.com/read/28936784/cryo-em-structures-of-the-mammalian-endo-lysosomal-trpml1-channel-elucidate-the-combined-regulation-mechanism
#1
Sensen Zhang, Ningning Li, Wenwen Zeng, Ning Gao, Maojun Yang
TRPML1 channel is a non-selective group-2 transient receptor potential (TRP) channel with Ca(2+) permeability. Located mainly in late endosome and lysosome of all mammalian cell types, TRPML1 is indispensable in the processes of endocytosis, membrane trafficking, and lysosome biogenesis. Mutations of TRPML1 cause a severe lysosomal storage disorder called mucolipidosis type IV (MLIV). In the present study, we determined the cryo-electron microscopy (cryo-EM) structures of Mus musculus TRPML1 (mTRPML1) in lipid nanodiscs and Amphipols...
September 21, 2017: Protein & Cell
https://www.readbyqxmd.com/read/28934222/endogenous-rgs14-is-a-cytoplasmic-nuclear-shuttling-protein-that-localizes-to-juxtanuclear-membranes-and-chromatin-rich-regions-of-the-nucleus
#2
Mary Rose Branch, John R Hepler
Regulator of G protein signaling 14 (RGS14) is a multifunctional scaffolding protein that integrates G protein and H-Ras/MAPkinase signaling pathways to regulate synaptic plasticity important for hippocampal learning and memory. However, to date, little is known about the subcellular distribution and roles of endogenous RGS14 in a neuronal cell line. Most of what is known about RGS14 cellular behavior is based on studies of tagged, recombinant RGS14 ectopically overexpressed in unnatural host cells. Here, we report for the first time a comprehensive assessment of the subcellular distribution and dynamic localization of endogenous RGS14 in rat B35 neuroblastoma cells...
2017: PloS One
https://www.readbyqxmd.com/read/28923947/tpc2-polymorphisms-associated-with-a-hair-pigmentation-phenotype-in-humans-result-in-gain-of-channel-function-by-independent-mechanisms
#3
Yu-Kai Chao, Verena Schludi, Cheng-Chang Chen, Elisabeth Butz, O N Phuong Nguyen, Martin Müller, Jens Krüger, Claudia Kammerbauer, Manu Ben-Johny, Angelika M Vollmar, Carola Berking, Martin Biel, Christian A Wahl-Schott, Christian Grimm
Two-pore channels (TPCs) are endolysosomal cation channels. Two members exist in humans, TPC1 and TPC2. Functional roles associated with the ubiquitously expressed TPCs include VEGF-induced neoangiogenesis, LDL-cholesterol trafficking and degradation, physical endurance under fasting conditions, autophagy regulation, the acrosome reaction in sperm, cancer cell migration, and intracellular trafficking of pathogens such as Ebola virus or bacterial toxins (e.g., cholera toxin). In a genome-wide association study for variants associated with human pigmentation characteristics two coding variants of TPC2, rs35264875 (encoding M484L) and rs3829241 (encoding G734E), have been found to be associated with a shift from brown to blond hair color...
September 18, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28922372/reduction-of-organelle-motility-by-removal-of-potassium-and-other-solutes
#4
John W Murray, David Yin, Allan W Wolkoff
There are surprisingly few studies that describe how the composition of cell culture medium may affect the trafficking of organelles. Here we utilize time lapse multi-channel fluorescent imaging to show that short term exposure of Huh-7 cells to medium lacking potassium, sodium, or chloride strongly reduces but does not eliminate the characteristic back and forth and cell-traversing movement of fluorescent EGF (FL-EGF) containing organelles. We focused on potassium because of its relatively low abundance in media and serum and its energy requiring accumulation into cells...
2017: PloS One
https://www.readbyqxmd.com/read/28921719/inflammation-alters-ampa-stimulated-calcium-responses-in-dorsal-striatal-d2-but-not-d1-spiny-projection-neurons
#5
Carissa D Winland, Nora Welsh, Alberto Sepulveda-Rodriguez, Stefano Vicini, Kathleen A Maguire-Zeiss
Neuroinflammation precedes neuronal loss in striatal neurodegenerative diseases and can be exacerbated by the release of proinflammatory molecules by microglia. These molecules can affect trafficking of AMPARs. The preferential trafficking of calcium-permeable versus impermeable AMPARs can result in disruptions of [Ca(2+) ]i and alter cellular functions. In striatal neurodegenerative diseases, changes in [Ca(2+) ]i and L-type voltage-gated calcium channels (VGCCs) have been reported. Therefore, the present study sought to determine whether a proinflammatory environment alters AMPA-stimulated [Ca(2+) ]i through calcium-permeable AMPARs and/or L-type VGCCs in dopamine-2 and dopamine-1 expressing striatal spiny projection neurons (D2 and D1 SPNs) in the dorsal striatum...
September 16, 2017: European Journal of Neuroscience
https://www.readbyqxmd.com/read/28912545/the-cacna1h-mutation-in-the-gaers-model-of-absence-epilepsy-enhances-t-type-ca-2-currents-by-altering-calnexin-dependent-trafficking-of-cav3-2-channels
#6
Juliane Proft, Yuriy Rzhepetskyy, Joanna Lazniewska, Fang-Xiong Zhang, Stuart M Cain, Terrance P Snutch, Gerald W Zamponi, Norbert Weiss
Low-voltage-activated T-type calcium channels are essential contributors to the functioning of thalamocortical neurons by supporting burst-firing mode of action potentials. Enhanced T-type calcium conductance has been reported in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and proposed to be causally related to the overall development of absence seizure activity. Here, we show that calnexin, an endoplasmic reticulum integral membrane protein, interacts with the III-IV linker region of the Cav3...
September 14, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28905383/leukoencephalopathy-causing-clcn2-mutations-are-associated-with-impaired-cl-channel-function-and-trafficking
#7
Héctor Gaitán-Peñas, Pirjo M Apaja, Tanit Arnedo, Aida Castellanos, Xabier Elorza-Vidal, David Soto, Xavier Gasull, Gergely L Lukacs, Raúl Estévez
Mutations in CLCN2 have been recently identified in patients suffering from a type of leukoencephalopathy involving intramyelinic oedema. Here, we characterised most of these mutations, which reduce the function of the chloride channel ClC-2 and impair its plasma membrane (PM) expression. Detailed biochemical and electrophysiological analyses of the Ala500Val mutation revealed that defective gating and increased cellular and PM turnover contributed to defective A500V-ClC-2 functional expression. Co-expression of the adhesion molecule GlialCAM, which forms a tertiary complex with ClC-2 and megalencephalic leukoencephalopathy with subcortical cyst 1 (MLC1), rescued the functional expression of the mutant by modifying its gating properties...
September 14, 2017: Journal of Physiology
https://www.readbyqxmd.com/read/28900914/stim-trp-pathways-and-microdomain-organization-contribution-of-trpc1-in-store-operated-ca-2-entry-impact-on-ca-2-signaling-and-cell-function
#8
Hwei Ling Ong, Indu S Ambudkar
Store-operated calcium entry (SOCE) is a ubiquitous Ca(2+) entry pathway that is activated in response to depletion of ER-Ca(2+) stores and critically controls the regulation of physiological functions in a wide variety of cell types. The transient receptor potential canonical (TRPC) channels (TRPCs 1-7), which are activated by stimuli leading to PIP2 hydrolysis, were first identified as molecular components of SOCE channels. While TRPC1 was associated with SOCE and regulation of function in several cell types, none of the TRPC members displayed I CRAC, the store-operated current identified in lymphocytes and mast cells...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28887112/protein-and-lipid-interactions-modulating-cftr-trafficking-and-rescue
#9
Carlos M Farinha, Elizabeth Miller, Nael McCarty
Different levels of CFTR regulation in the cell contribute to a stringent control of chloride secretion in epithelia. Tuning of chloride transport is achieved by modulating CFTR biogenesis, exit from the endoplasmic reticulum, trafficking, membrane stability and channel activity. In this short review, we summarize recent findings identifying interactions with other proteins - directly or through membrane lipids - and briefly discuss how these observations can provide clues to the design of better therapeutic approaches...
September 5, 2017: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
https://www.readbyqxmd.com/read/28878632/the-influence-of-regional-distribution-and-pharmacologic-specificity-of-gabaar-subtype-expression-on-anesthesia-and-emergence
#10
REVIEW
Iris Speigel, Edyta K Bichler, Paul S García
Anesthetics produce unconsciousness by modulating ion channels that control neuronal excitability. Research has shown that specific GABAA receptor (GABAAR) subtypes in particular regions of the central nervous system contribute to different hyperpolarizing conductances, and behaviorally to distinct components of the anesthetized state. The expression of these receptors on the neuron cell surface, and thus the strength of inhibitory neurotransmission, is dynamically regulated by intracellular trafficking mechanisms...
2017: Frontiers in Systems Neuroscience
https://www.readbyqxmd.com/read/28877958/proline-dependent-and-basophilic-kinases-phosphorylate-human-trpc6-at-serine-14-to-control-channel-activity-through-increased-membrane-expression
#11
Henning Hagmann, Nicole Mangold, Markus M Rinschen, Tim Koenig, Karl Kunzelmann, Bernhard Schermer, Thomas Benzing, Paul T Brinkkoetter
Signaling via the transient receptor potential (TRP) ion channel C6 plays a pivotal role in hereditary and sporadic glomerular kidney disease. Several studies have identified gain-of-function mutations of TRPC6 and report induced expression and enhanced channel activity of TRPC6 in association with glomerular diseases. Interfering with TRPC6 activity may open novel therapeutic pathways. TRPC6 channel activity is controlled by protein expression and stability as well as intracellular trafficking. Identification of regulatory phosphorylation sites in TRPC6 and corresponding protein kinases is essential to understand the regulation of TRPC6 activity and may result in future therapeutic strategies...
September 6, 2017: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/28877240/runx1-mediates-the-development-of-the-granular-convoluted-tubules-in-the-submandibular-glands
#12
Hitomi Ono Minagi, Safiye Esra Sarper, Hiroshi Kurosaka, Koh-Ichi Kuremoto, Ichiro Taniuchi, Takayoshi Sakai, Takashi Yamashiro
The mouse granular convoluted tubules (GCTs), which are only located in the submandibular gland (SMG) are known to develop and maintain their structure in an androgen-dependent manner. We previously demonstrated that the GCTs are involuted by the epithelial deletion of core binding factor β (CBFβ), a transcription factor that physically interacts with any of the Runt-related transcription factor (RUNX) proteins (RUNX1, 2 and 3). This result clearly demonstrates that the Runx /Cbfb signaling pathway is indispensable in the development of the GCTs...
2017: PloS One
https://www.readbyqxmd.com/read/28869532/cftr-nherf2-lpa%C3%A2-complex-in-the-airway-and-gut-epithelia
#13
REVIEW
Weiqiang Zhang, Zhihong Zhang, Yanhui Zhang, Anjaparavanda P Naren
The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP- and cGMP-regulated chloride (Cl(-)) and bicarbonate (HCO₃(-)) channel localized primarily at the apical plasma membrane of epithelial cells lining the airway, gut and exocrine glands, where it is responsible for transepithelial salt and water transport. Several human diseases are associated with altered CFTR channel function. Cystic fibrosis (CF) is caused by the absence or dysfunction of CFTR channel activity, resulting from mutations in the gene...
September 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28860469/prolonged-at1r-activation-induces-cav1-2-channel-internalization-in-rat-cardiomyocytes
#14
Tamara Hermosilla, Matías Encina, Danna Morales, Cristian Moreno, Carolina Conejeros, Hilda M Alfaro-Valdés, Felipe Lagos-Meza, Felipe Simon, Christophe Altier, Diego Varela
The cardiac L-type calcium channel is a multi-subunit complex that requires co-assembling of the pore-forming subunit CaV1.2 with auxiliary subunits CaVα2δ and CaVβ. Its traffic has been shown to be controlled by these subunits and by the activation of various G-protein coupled receptors (GPCR). Here, we explore the consequences of the prolonged activation of angiotensin receptor type 1 (AT1R) over CaV1.2 channel trafficking. Bioluminescence Resonance Energy Transfer (BRET) assay between β-arrestin and L-type channels in angiotensin II-stimulated cells was used to assess the functional consequence of AT1R activation, while immunofluorescence of adult rat cardiomyocytes revealed the effects of GPCR activation on CaV1...
August 31, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28859335/a-new-mutation-in-fig4-causes-a-severe-form-of-cmt4j-involving-trpv4-in-the-pathogenic-cascade
#15
Benoit J Gentil, Erin O'Ferrall, Colin Chalk, Luis F Santana, Heather D Durham, Rami Massie
Mutations in FIG4, coding for a phosphoinositol(3,5) bisphosphate 5' phosphatase and involved in vesicular trafficking and fusion, have been shown causing a recessive form of Charcot-Marie-Tooth (CMT). We have identified a novel intronic mutation in the FIG4 in a wheel-chair bound patient presenting with a severe form of CMT4J and provide a longitudinal study. Investigations indicated a demyelinating sensorimotor polyneuropathy with diffuse active denervation and severe axonal loss. Genetic testing revealed that the patient is heterozygous for 2 FIG4 mutations, p...
September 1, 2017: Journal of Neuropathology and Experimental Neurology
https://www.readbyqxmd.com/read/28856727/cholesterol-regulates-polymodal-sensory-transduction-in-m%C3%A3-ller-glia
#16
Monika Lakk, Oleg Yarishkin, Jackson M Baumann, Anthony Iuso, David Križaj
Over- and underexposure to cholesterol activates glia in neurodegenerative brain and retinal diseases but the molecular targets of cholesterol in glial cells are not known. Here, we report that disruption of unesterified membrane cholesterol content modulates the transduction of chemical, mechanical and temperature stimuli in mouse Müller cells. Activation of TRPV4 (transient receptor potential vanilloid type 4), a nonselective polymodal cation channel was studied following the removal or supplementation of cholesterol using the methyl-beta cyclodextrin (MβCD) delivery vehicle...
August 30, 2017: Glia
https://www.readbyqxmd.com/read/28855648/the-two-pore-channel-tpc1-is-required-for-efficient-protein-processing-through-early-and-recycling-endosomes
#17
Jan Castonguay, Joachim H C Orth, Thomas Müller, Faten Sleman, Christian Grimm, Christian Wahl-Schott, Martin Biel, Robert Theodor Mallmann, Wolfgang Bildl, Uwe Schulte, Norbert Klugbauer
Two-pore channels (TPCs) are localized in endo-lysosomal compartments and assumed to play an important role for vesicular fusion and endosomal trafficking. Recently, it has been shown that both TPC1 and 2 were required for host cell entry and pathogenicity of Ebola viruses. Here, we investigate the cellular function of TPC1 using protein toxins as model substrates for distinct endosomal processing routes. Toxin uptake and activation through early endosomes but not processing through other compartments were reduced in TPC1 knockout cells...
August 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28835336/neutrophil-membrane-cholesterol-content-is-a-key-factor-in-cystic-fibrosis-lung-disease
#18
Michelle M White, Patrick Geraghty, Elaine Hayes, Stephen Cox, William Leitch, Bader Alfawaz, Gillian M Lavelle, Oliver J McElvaney, Ryan Flannery, Joanne Keenan, Paula Meleady, Michael Henry, Martin Clynes, Cedric Gunaratnam, Noel G McElvaney, Emer P Reeves
BACKGROUND: Identification of mechanisms promoting neutrophil trafficking to the lungs of patients with cystic fibrosis (CF) is a challenge for next generation therapeutics. Cholesterol, a structural component of neutrophil plasma membranes influences cell adhesion, a key step in transmigration. The effect of chronic inflammation on neutrophil membrane cholesterol content in patients with CF (PWCF) remains unclear. To address this we examined neutrophils of PWCF to evaluate the cause and consequence of altered membrane cholesterol and identified the effects of lung transplantation and ion channel potentiator therapy on the cellular mechanisms responsible for perturbed membrane cholesterol and increased cell adhesion...
August 16, 2017: EBioMedicine
https://www.readbyqxmd.com/read/28806752/the-escrt-iii-pathway-facilitates-cardiomyocyte-release-of-cbin1-containing-microparticles
#19
Bing Xu, Ying Fu, Yan Liu, Sosse Agvanian, Robert C Wirka, Rachel Baum, Kang Zhou, Robin M Shaw, TingTing Hong
Microparticles (MPs) are cell-cell communication vesicles derived from the cell surface plasma membrane, although they are not known to originate from cardiac ventricular muscle. In ventricular cardiomyocytes, the membrane deformation protein cardiac bridging integrator 1 (cBIN1 or BIN1+13+17) creates transverse-tubule (t-tubule) membrane microfolds, which facilitate ion channel trafficking and modulate local ionic concentrations. The microfold-generated microdomains continuously reorganize, adapting in response to stress to modulate the calcium signaling apparatus...
August 2017: PLoS Biology
https://www.readbyqxmd.com/read/28805732/the-mechanistic-links-between-insulin-and-cystic-fibrosis-transmembrane-conductance-regulator-cftr-cl-channel
#20
REVIEW
Yoshinori Marunaka
The cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel belongs to the ATP-binding cassette (ABC) transporter superfamily and regulates Cl(-) secretion in epithelial cells for water secretion. Loss-of-function mutations to the CFTR gene cause dehydrated mucus on the apical side of epithelial cells and increase the susceptibility of bacterial infection, especially in the airway and pulmonary tissues. Therefore, research on the molecular properties of CFTR, such as its gating mechanism and subcellular trafficking, have been intensively pursued...
August 14, 2017: International Journal of Molecular Sciences
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