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Ion channel disease

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https://www.readbyqxmd.com/read/28727426/fully-atomistic-a%C3%AE-40-and-a%C3%AE-42-oligomers-in-water-observation-of-pore-like-conformations
#1
Matthew John Voelker, Bogdan Barz, Brigita Urbanc
Oligomers formed by amyloid β-protein (Aβ) are central to Alzheimer's disease (AD) pathology, yet their structure remains elusive. Of the two predominant Aβ alloforms, Aβ40 and Aβ42, the latter is more strongly associated with AD. Here, we structurally characterized Aβ40 and Aβ42 monomers through pentamers which were converted from previously derived coarse-grained (DMD4B-HYDRA) simulations into all-atom conformations and subjected to explicit-solvent MD. Free energy landscapes revealed that structural differences between Aβ40 and Aβ42 conformations increase with oligomer order up to trimers...
July 20, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28726848/patch-clamp-technique-to-characterize-ion-channels-in-enlarged-individual-endolysosomes
#2
Cheng-Chang Chen, Chunlei Cang, Stefanie Fenske, Elisabeth Butz, Yu-Kai Chao, Martin Biel, Dejian Ren, Christian Wahl-Schott, Christian Grimm
According to proteomics analyses, more than 70 different ion channels and transporters are harbored in membranes of intracellular compartments such as endosomes and lysosomes. Malfunctioning of these channels has been implicated in human diseases such as lysosomal storage disorders, neurodegenerative diseases and metabolic pathologies, as well as in the progression of certain infectious diseases. As a consequence, these channels have engendered very high interest as future drug targets. Detailed electrophysiological characterization of intracellular ion channels is lacking, mainly because standard methods to analyze plasma membrane ion channels, such as the patch-clamp technique, are not readily applicable to intracellular organelles...
August 2017: Nature Protocols
https://www.readbyqxmd.com/read/28725634/ip3-receptor-mediated-calcium-signaling-and-its-role-in-autophagy-in-cancer
#3
REVIEW
Elzbieta Kania, Gemma Roest, Tim Vervliet, Jan B Parys, Geert Bultynck
Calcium ions (Ca(2+)) play a complex role in orchestrating diverse cellular processes, including cell death and survival. To trigger signaling cascades, intracellular Ca(2+) is shuffled between the cytoplasm and the major Ca(2+) stores, the endoplasmic reticulum (ER), the mitochondria, and the lysosomes. A key role in the control of Ca(2+) signals is attributed to the inositol 1,4,5-trisphosphate (IP3) receptors (IP3Rs), the main Ca(2+)-release channels in the ER. IP3Rs can transfer Ca(2+) to the mitochondria, thereby not only stimulating core metabolic pathways but also increasing apoptosis sensitivity and inhibiting basal autophagy...
2017: Frontiers in Oncology
https://www.readbyqxmd.com/read/28725222/neuronal-surface-autoantibodies-in-neuropsychiatric-disorders-are-there-implications-for-depression
#4
REVIEW
Shenghua Zong, Carolin Hoffmann, Marina Mané-Damas, Peter Molenaar, Mario Losen, Pilar Martinez-Martinez
Autoimmune diseases are affecting around 7.6-9.4% of the general population. A number of central nervous system disorders, including encephalitis and severe psychiatric disorders, have been demonstrated to associate with specific neuronal surface autoantibodies (NSAbs). It has become clear that specific autoantibodies targeting neuronal surface antigens and ion channels could cause severe mental disturbances. A number of studies have focused or are currently investigating the presence of autoantibodies in specific mental conditions such as schizophrenia and bipolar disorders...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28724750/disruption-of-a-structurally-important-extracellular-element-in-the-glycine-receptor-leads-to-decreased-synaptic-integration-and-signaling-resulting-in-severe-startle-disease
#5
Natascha Schaefer, Alexandra Berger, Johannes van Brederode, Fang Zheng, Yan Zhang, Sophie Leacock, Laura Littau, Sibylle Jablonka, Sony Malhotra, Maya Topf, Friederike Winter, Daria Davydova, Joseph W Lynch, Christopher J Paige, Christian Alzheimer, Robert J Harvey, Carmen Villmann
Functional impairments or trafficking defects of inhibitory glycine receptors (GlyRs) have been linked to human hyperekplexia/startle disease and autism spectrum disorder. We found that lack of synaptic integration of GlyRs, together with disrupted receptor function is responsible for a lethal startle phenotype in a novel spontaneous mouse mutant shaky, caused by a missense mutation Q177K located in the extracellular β8-β9 loop of the GlyR α1 subunit. Recently, structural data provided evidence that the flexibility of the β8-β9 loop is crucial for conformational transitions during opening and closing of the ion channel and represents a novel allosteric binding site in cys-loop receptors...
July 19, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28720769/concentration-dependent-binding-of-small-ligands-to-multiple-saturable-sites-in-membrane-proteins
#6
Letícia Stock, Juliana Hosoume, Werner Treptow
Membrane proteins are primary targets for most therapeutic indications in cancer and neurological diseases, binding over 50% of all known small molecule drugs. Understanding how such ligands impact membrane proteins requires knowledge on the molecular structure of ligand binding, a reasoning that has driven relentless efforts in drug discovery and translational research. Binding of small ligands appears however highly complex involving interaction to multiple transmembrane protein sites featuring single or multiple occupancy states...
July 18, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28718820/a-transcriptomic-survey-of-ion-channel-based-conotoxins-in-the-chinese-tubular-cone-snail-conus-betulinus
#7
Yu Huang, Chao Peng, Yunhai Yi, Bingmiao Gao, Qiong Shi
Conotoxins in the venom of cone snails (Conus spp.) are a mixture of active peptides that work as blockers, agonists, antagonists, or inactivators of various ion channels. Recently we reported a high-throughput method to identify 215 conotoxin transcripts from the Chinese tubular cone snail, C. betulinus. Here, based on the previous datasets of four transcriptomes from three venom ducts and one venom bulb, we explored ion channel-based conotoxins and predicted their related ion channel receptors. Homologous analysis was also performed for the most abundant ion channel protein, voltage-gated potassium (Kv; with Kv1...
July 18, 2017: Marine Drugs
https://www.readbyqxmd.com/read/28713772/harnessing-neutrophil-survival-mechanisms-during-chronic-infection-by-pseudomonas-aeruginosa-novel-therapeutic-targets-to-dampen-inflammation-in-cystic-fibrosis
#8
REVIEW
Benoît S Marteyn, Pierre-Régis Burgel, Laurent Meijer, Véronique Witko-Sarsat
More than two decades after cloning the cystic fibrosis transmembrane regulator (CFTR) gene, the defective gene in cystic fibrosis (CF), we still do not understand how dysfunction of this ion channel causes lung disease and the tremendous neutrophil burden which persists within the airways; nor why chronic colonization by Pseudomonas aeruginosa develops in CF patients who are thought to be immunocompetent. It appears that the microenvironment within the lung of CF patients provides favorable conditions for both P...
2017: Frontiers in Cellular and Infection Microbiology
https://www.readbyqxmd.com/read/28713289/mitochondrial-vdac1-a-key-gatekeeper-as-potential-therapeutic-target
#9
REVIEW
Amadou K S Camara, YiFan Zhou, Po-Chao Wen, Emad Tajkhorshid, Wai-Meng Kwok
Mitochondria are the key source of ATP that fuels cellular functions, and they are also central in cellular signaling, cell division and apoptosis. Dysfunction of mitochondria has been implicated in a wide range of diseases, including neurodegenerative and cardiac diseases, and various types of cancer. One of the key proteins that regulate mitochondrial function is the voltage-dependent anion channel 1 (VDAC1), the most abundant protein on the outer membrane of mitochondria. VDAC1 is the gatekeeper for the passages of metabolites, nucleotides, and ions; it plays a crucial role in regulating apoptosis due to its interaction with apoptotic and anti-apoptotic proteins, namely members of the Bcl-2 family of proteins and hexokinase...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28713282/the-n-terminal-region-of-the-ryanodine-receptor-affects-channel-activation
#10
Andrea Faltinova, Nataša Tomaskova, Marián Antalik, Jozef Sevcik, Alexandra Zahradnikova
Mutations in the cardiac ryanodine receptor (RyR2), the ion channel responsible for release of calcium ions from intracellular stores into cytoplasm, are the cause of several inherited cardiac arrhythmias. At the molecular level, disease symptoms can be mimicked by domain peptides from mutation-prone regions of RyR2 that bind to RyR2 and activate it. Here we show that the domain peptide DPcpvtN2, corresponding to the central helix of the N-terminal region of RyR2, activates the RyR2 channel. Structural modeling of interaction between DPcpvtN2 and the N-terminal region of RyR2 in the closed and open conformation provided three plausible structures of the complex...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28707396/role-of-abnormal-repolarization-in-the-mechanism-of-cardiac-arrhythmia
#11
O E Osadchii
In cardiac patients, life-threatening tachyarrhythmia is often precipitated by abnormal changes in ventricular repolarization and refractoriness. Repolarization abnormalities typically evolve as a consequence of impaired function of outward K(+) currents in cardiac myocytes, which may be caused by genetic defects or result from various acquired pathophysiological conditions, including electrical remodelling in cardiac disease, ion channel modulation by clinically used pharmacological agents, and systemic electrolyte disorders seen in heart failure, such as hypokalaemia...
July 2017: Acta Physiologica
https://www.readbyqxmd.com/read/28702845/regulation-of-cardiac-ca-2-and-ion-channels-by-shear-mechanotransduction
#12
REVIEW
Joon-Chul Kim, Min-Jeong Son, Jun Wang, Sun-Hee Woo
Cardiac contraction is controlled by a Ca(2+) signaling sequence that includes L-type Ca(2+) current-gated opening of Ca(2+) release channels (ryanodine receptors) in the sarcoplasmic reticulum (SR). Local Ca(2+) signaling in the atrium differs from that in the ventricle because atrial myocytes lack transverse tubules and have more abundant corbular SR. Myocardium is subjected to a variety of forces with each contraction, such as stretch, shear stress, and afterload, and adapts to those mechanical stresses...
July 12, 2017: Archives of Pharmacal Research
https://www.readbyqxmd.com/read/28701749/calcium-activated-sk-channels-control-firing-regularity-by-modulating-sodium-channel-availability-in-midbrain-dopamine-neurons
#13
Rajeshwari Iyer, Mark A Ungless, Aldo A Faisal
Dopamine neurons in the substantia nigra pars compacta and ventral tegmental area regulate behaviours such as reward-related learning, and motor control. Dysfunction of these neurons is implicated in Schizophrenia, addiction to drugs, and Parkinson's disease. While some dopamine neurons fire single spikes at regular intervals, others fire irregular single spikes interspersed with bursts. Pharmacological inhibition of calcium-activated potassium (SK) channels increases the variability in their firing pattern, sometimes also increasing the number of spikes fired in bursts, indicating that SK channels play an important role in maintaining dopamine neuron firing regularity and burst firing...
July 12, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28697919/fatty-acid-translocase-promoted-hepatitis-b-virus-replication-by-upregulating-the-levels-of-hepatic-cytosolic-calcium
#14
Jian Huang, Lei Zhao, Ping Yang, Zhen Chen, Xiong Z Ruan, Ailong Huang, Ni Tang, Yaxi Chen
Hepatitis B virus (HBV) is designated a "metabolovirus" due to the intimate connection between the virus and host metabolism. The nutrition state of the host plays a relevant role in the severity of HBV infection. Metabolic syndrome (MS) is prone to increasing HBV DNA loads and accelerating the progression of liver disease in patients with chronic hepatitis B (CHB). Cluster of differentiation 36 (CD36), also named fatty acid translocase, is known to facilitate long-chain fatty acid uptake and contribute to the development of MS...
July 8, 2017: Experimental Cell Research
https://www.readbyqxmd.com/read/28696497/role-of-ca2-and-ion-channels-in-the-regulation-of-apoptosis-under-hypoxia
#15
REVIEW
Miaohong Wang, Jin Tan, Yuyang Miao, Mengmeng Li, Qiang Zhang
Hypoxia is a kind of common pathological condition existing in various diseases such as sleep apnea syndrome, myocardial infarction and stroke, which can precipitate the onset of diseases through inducing cell apoptosis. Ca²⁺ is the ubiquitous message in cell. Given the crucial role of Ca2²⁺ in physiology, intracellular Ca²⁺ overload is a significant regulator of apoptosis. Numerous experiments show that hypoxia may cause changes of multiple cellular Ca²⁺ channels, for instance, Na⁺/ Ca²⁺ Exchanger (NCX), L-type voltage dependent Ca²⁺ channel (L-VDCC), inositol triphosphate receptors (IP3R) and so on, which contribute to intracellular Ca²⁺ overload, thus eventually triggering cell apoptosis...
July 11, 2017: Histology and Histopathology
https://www.readbyqxmd.com/read/28689026/venom-peptides-as-pharmacological-tools-and-therapeutics-for-diabetes
#16
REVIEW
Samuel D Robinson, Helena Safavi-Hemami
Diabetes mellitus is a chronic disease caused by a deficiency in production of insulin by the beta cells of the pancreas (type 1 diabetes, T1D), or by partial deficiency of insulin production and the ineffectiveness of the insulin produced (type 2 diabetes, T2D). Animal venoms are a unique source of compounds targeting ion channels and receptors in the nervous and cardiovascular systems. In recent years, several venom peptides have also emerged as pharmacological tools and therapeutics for T1D and T2D. Some of these peptides act directly as mimics of endogenous metabolic hormones while others act on ion channels expressed in pancreatic beta cells...
July 5, 2017: Neuropharmacology
https://www.readbyqxmd.com/read/28686597/altered-paracellular-cation-permeability-due-to-a-rare-cldn10b-variant-causes-anhidrosis-and-kidney-damage
#17
Joakim Klar, Jörg Piontek, Susanne Milatz, Muhammad Tariq, Muhammad Jameel, Tilman Breiderhoff, Jens Schuster, Ambrin Fatima, Maria Asif, Muhammad Sher, Katrin Mäbert, Anja Fromm, Shahid M Baig, Dorothee Günzel, Niklas Dahl
Claudins constitute the major component of tight junctions and regulate paracellular permeability of epithelia. Claudin-10 occurs in two major isoforms that form paracellular channels with ion selectivity. We report on two families segregating an autosomal recessive disorder characterized by generalized anhidrosis, severe heat intolerance and mild kidney failure. All affected individuals carry a rare homozygous missense mutation c.144C>G, p.(N48K) specific for the claudin-10b isoform. Immunostaining of sweat glands from patients suggested that the disease is associated with reduced levels of claudin-10b in the plasma membranes and in canaliculi of the secretory portion...
July 2017: PLoS Genetics
https://www.readbyqxmd.com/read/28684697/transient-receptor-potential-trp-channels-in-drug-discovery-old-concepts-new-thoughts
#18
EDITORIAL
Susan Huang, Arpad Szallasi
2017 marks the 20th anniversary of the molecular cloning by David Julius and colleagues (1997) of the long sought-after capsaicin receptor, now known as TRPV1 (Transient Receptor Potential Vanilloid 1) [1]. This seminal discovery has opened up a "hot" new field of basic research and launched drug discovery efforts into the large family (by the latest count 28 mammalian members, 27 in humans) of TRP ion channels [2]. Indeed, it took less than a decade for the first potent, small molecule TRPV1 antagonists to enter phase 1 clinical trials [3]...
July 6, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28680407/cardiac-ion-channel-regulation-in-obesity-and-the-metabolic-syndrome-relevance-to-long-qt-syndrome-and-atrial-fibrillation
#19
REVIEW
Ademuyiwa S Aromolaran, Mohamed Boutjdir
Obesity and its associated metabolic dysregulation leading to metabolic syndrome is an epidemic that poses a significant public health problem. More than one-third of the world population is overweight or obese leading to enhanced risk of cardiovascular disease (CVD) incidence and mortality. Obesity predisposes to atrial fibrillation, ventricular, and supraventricular arrhythmias; conditions that are underlain by dysfunction in electrical activity of the heart. To date, current therapeutic options for cardiomyopathy of obesity are limited, suggesting that there is considerable room for development of therapeutic interventions with novel mechanisms of action that will help normalize rhythm in obese patients...
2017: Frontiers in Physiology
https://www.readbyqxmd.com/read/28679281/lipid-mediated-modulation-of-intracellular-ion-channels-and-redox-state-physio-pathological-implications
#20
Marisa Brini, Luigi Leanza, Ildiko Szabo
<i>Significance</i>: Ion channels play an important role in the regulation of organelle function within the cell, as proven by increasing evidence pointing to a link between altered function of intracellular ion channels and different pathologies ranging from cancer to neurodegenerative diseases, ischemic damage and lysosomal storage diseases. <i>Recent Advances</i>: A link between these pathologies and redox state as well as lipid homeostasis and ion channel function is in the focus of current research...
July 5, 2017: Antioxidants & Redox Signaling
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