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Ion channel disease

Xuan-Rui Zhang, You-Ping Xu, Xin-Zhong Cai
Mechanisms underlying plant non-host resistance to Xanthomonas oryzae pv. oryzicola ( Xoc ), the pathogen causing rice leaf streak disease, are largely unknown. Cyclic nucleotide-gated ion channels (CNGCs) are calcium-permeable channels that are involved in various biological processes including plant resistance. In this study, functions of two tomato CNGC genes SlCNGC1 and SlCNGC14 in non-host resistance to Xoc were analyzed. Silencing of SlCNGC1 and SlCNGC14 in tomato significantly enhanced Xoc -induced hypersensitive response (HR) and non-host resistance, demonstrating that both SlCNGC1 and SlCNGC14 negatively regulate non-host resistance related HR and non-host resistance to Xoc in tomato...
2018: Frontiers in Plant Science
Monika Lakk, Felix Vazquez-Chona, Oleg Yarishkin, David Križaj
Unesterified cholesterol controls the fluidity, permeability and electrical properties of eukaryotic cell membranes. Consequently, cholesterol levels in the retina and the brain are tightly regulated whereas depletion or oversupply caused by diet or heredity contribute to neurodegenerative diseases and vision loss. Astroglia play a central role in the biosynthesis, uptake and transport of cholesterol and also drive inflammatory signaling under hypercholesterolemic conditions associated with high-fat diet (diabetes) and neurodegenerative disease...
February 2018: Neural Regeneration Research
Chun-Hsiang Tan, Peter A McNaughton
The abilities to detect warmth and heat are critical for the survival of all animals, both in order to be able to identify suitable thermal environments for the many different activities essential for life and to avoid damage caused by extremes of temperature. Several ion channels belonging to the TRP family are activated by non-noxious warmth or by heat and are therefore plausible candidates for thermal detectors, but identifying those that actually regulate warmth and heat detection in intact animals has proven problematic...
March 19, 2018: Pflügers Archiv: European Journal of Physiology
Jianjun Chang, Yan Ding, Zhiyu Zhou, Hong-Guang Nie, Hong-Long Ji
Transepithelial fluid and salt re-absorption in epithelial tissues play an important role in fluid and salt homeostasis. In absorptive epithelium, fluid and salt flux is controlled by machinery mainly composed of epithelial sodium channels (ENaC), cystic fibrosis transmembrane conductance regulator (CFTR), Na⁺/H⁺ exchanger (NHE), aquaporin, and sodium potassium adenosine triphosphatase (Na⁺/K⁺-ATPase). Dysregulation of fluid and salt transport across epithelium contributes to the pathogenesis of many diseases, such as pulmonary edema and cystic fibrosis...
March 16, 2018: International Journal of Molecular Sciences
Barbara Wiśniowska, Sebastian Polak
The current study is an example of drug-disease interaction modeling where a drug induces a condition which can affect the pharmacodynamics of other concomitantly taken drugs. The electrophysiological effects of hypokaliemia and heart rate changes induced by the antiasthmatic drugs were simulated with the use of the cardiac safety simulator. Biophysically detailed model of the human cardiac physiology-ten Tusscher ventricular cardiomyocyte cell model-was employed to generate pseudo-ECG signals and QTc intervals for 44 patients from four clinical studies...
March 15, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Mirko Moroni, M Rocio Servin-Vences, Raluca Fleischer, Oscar Sánchez-Carranza, Gary R Lewin
Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage-gated mode. Mutations that cause human diseases, such as xerocytosis, profoundly shift voltage sensitivity of PIEZO1 channels toward the resting membrane potential and strongly promote voltage gating. Voltage modulation may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation...
March 15, 2018: Nature Communications
Domenique D Zomer-van Ommen, Eyleen de Poel, Evelien Kruisselbrink, Hugo Oppelaar, Annelotte M Vonk, Hettie M Janssens, Cornelis K van der Ent, Marne C Hagemeijer, Jeffrey M Beekman
BACKGROUND: New functional assays using primary human intestinal adult stem cell cultures can be valuable tools to study epithelial defects in human diseases such as cystic fibrosis. METHODS: CFTR-mediated ion transport was measured in rectal organoid-derived monolayers grown from subjects with various CFTR mutations and compared to donor-matched intestinal current measurements (ICM) in rectal biopsies and forskolin-induced swelling of rectal organoids. RESULTS: Rectal organoid-derived monolayers were generated within four days...
March 13, 2018: Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society
Nikunjkumar Patel, Oliver Hatley, Alexander Berg, Klaus Romero, Barbara Wisniowska, Debra Hanna, David Hermann, Sebastian Polak
Drug-induced cardiac arrhythmia, especially occurrence of torsade de pointes (TdP), has been a leading cause of attrition and post-approval re-labeling and withdrawal of many drugs. TdP is a multifactorial event, reflecting more than just drug-induced cardiac ion channel inhibition and QT interval prolongation. This presents a translational gap in extrapolating pre-clinical and clinical cardiac safety assessment to estimate TdP risk reliably, especially when the drug of interest is used in combination with other QT-prolonging drugs for treatment of diseases such as tuberculosis...
March 14, 2018: AAPS Journal
Tanziyah Muqeem, Biswarup Ghosh, Vitor Pinto, Angelo C Lepore, Manuel Covarrubias
Presynaptic voltage-gated K+ (Kv) channels in dorsal root ganglion (DRG) neurons are thought to regulate nociceptive synaptic transmission in the spinal dorsal horn. However, the Kv channel subtypes responsible for this critical role have not been identified. The Kv3.4 channel is particularly important because it is robustly expressed in DRG nociceptors, where it regulates action potential (AP) duration. Furthermore, Kv3.4 dysfunction is implicated in the pathophysiology of neuropathic pain in multiple pain models...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Hyoung Kyu Kim, Michael Huy Cuong Pham, Kyung Soo Ko, Byoung Doo Rhee, Jin Han
Alternative splicing (AS) of protein-coding messenger RNAs is an essential regulatory mechanism in eukaryotic gene expression that controls the proper function of proteins. It is also implicated in the physiological regulation of mitochondria and various ion channels. Considering that mis-splicing can result in various human diseases by modifying or abrogating important physiological protein functions, a fine-tuned balance of AS is essential for human health. Accumulated data highlight the importance of alternatively spliced isoforms in various diseases, including neurodegenerative disorders, cancer, immune and infectious diseases, cardiovascular diseases, and metabolic conditions...
March 13, 2018: Pflügers Archiv: European Journal of Physiology
Zhihan Zhao, Huan Lan, Ibrahim El-Battrawy, Xin Li, Fanis Buljubasic, Katherine Sattler, Gökhan Yücel, Siegfried Lang, Malte Tiburcy, Wolfram-Hubertus Zimmermann, Lukas Cyganek, Jochen Utikal, Thomas Wieland, Martin Borggrefe, Xiao-Bo Zhou, Ibrahim Akin
Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are providing new possibilities for the biological study, cell therapies, and drug discovery. However, the ion channel expression and functions as well as regulations in hiPSC-CMs still need to be fully characterized. Methods: Cardiomyocytes were derived from hiPS cells that were generated from two healthy donors. qPCR and patch clamp techniques were used for the study. Results: In addition to the reported ion channels, INa , ICa-L , ICa-T , If , INCX , IK1 , Ito , IKr , IKs IKATP , IK-pH , ISK1-3 , and ISK4 , we detected both the expression and currents of ACh-activated (KACh) and Na+ -activated (KNa) K+ , volume-regulated and calcium-activated (Cl-Ca) Cl- , and TRPV channels...
2018: Stem Cells International
Paolo Severino, Andrea D'Amato, Lucrezia Netti, Mariateresa Pucci, Marialaura De Marchis, Raffaele Palmirotta, Maurizio Volterrani, Massimo Mancone, Francesco Fedele
Diabetes mellitus is one the strongest risk factors for cardiovascular disease and, in particular, for ischemic heart disease (IHD). The pathophysiology of myocardial ischemia in diabetic patients is complex and not fully understood: some diabetic patients have mainly coronary stenosis obstructing blood flow to the myocardium; others present with coronary microvascular disease with an absence of plaques in the epicardial vessels. Ion channels acting in the cross-talk between the myocardial energy state and coronary blood flow may play a role in the pathophysiology of IHD in diabetic patients...
March 10, 2018: International Journal of Molecular Sciences
Hui Huang, Georg Kuenze, Jarrod A Smith, Keenan C Taylor, Amanda M Duran, Arina Hadziselimovic, Jens Meiler, Carlos G Vanoye, Alfred L George, Charles R Sanders
Mutations that induce loss of function (LOF) or dysfunction of the human KCNQ1 channel are responsible for susceptibility to a life-threatening heart rhythm disorder, the congenital long QT syndrome (LQTS). Hundreds of KCNQ1 mutations have been identified, but the molecular mechanisms responsible for impaired function are poorly understood. We investigated the impact of 51 KCNQ1 variants with mutations located within the voltage sensor domain (VSD), with an emphasis on elucidating effects on cell surface expression, protein folding, and structure...
March 2018: Science Advances
Jessica M de Souza, Bruno D C Goncalves, Marcus V Gomez, Luciene B Vieira, Fabiola M Ribeiro
Neurodegenerative diseases affect millions of individuals worldwide. So far, no disease-modifying drug is available to treat patients, making the search for effective drugs an urgent need. Neurodegeneration is triggered by the activation of several cellular processes, including oxidative stress, mitochondrial impairment, neuroinflammation, aging, aggregate formation, glutamatergic excitotoxicity, and apoptosis. Therefore, many research groups aim to identify drugs that may inhibit one or more of these events leading to neuronal cell death...
2018: Frontiers in Pharmacology
Lina A Matschke, Susanne Rinné, Terrance P Snutch, Wolfgang H Oertel, Amalia M Dolga, Niels Decher
The physiological, intrinsic activity of noradrenergic locus coeruleus (LC) neurons is important for the control of sleep/wakefulness, cognition and autonomous body functions. Dysregulations of the LC-noradrenergic network contribute to the pathogenesis of psychiatric disorders and are key findings in early stages of neurodegenerative diseases. Therefore, identifying ion channels mediating the intrinsic pacemaking mechanism of LC neurons, which is in turn directly coupled to Ca2+ homeostasis and cell survival signaling pathways, can help to foster our understanding of the vulnerability of these neurons in neurodegenerative diseases...
March 7, 2018: Molecular and Cellular Neurosciences
Catherine E Lipovsky, Brittany D Brumback, Aditi Khandekar, Stacey L Rentschler
The left and right ventricles of the four-chambered heart have distinct developmental origins and functions. Chamber-specific developmental programming underlies the differential gene expression of ion channel subunits regulating cardiac electrophysiology that persists into adulthood. Here, we discuss regional specific electrical responses to genetic mutations and cardiac stressors, their clinical correlations, and describe many of the multi-scale techniques commonly used to analyze electrophysiological regional heterogeneity...
March 8, 2018: Journal of Cardiovascular Development and Disease
Fernando A L Marson
PURPOSE OF REVIEW: To compile data from the past 10 years regarding the role of modifying genes in cystic fibrosis (CF). RECENT FINDINGS: CF is a model disease for understanding of the action of modifying genes. Although it is a monogenic (CFTR) autosomal recessive disease, CF presents with wide phenotypic variability. In CF, variability occurs with different intensity among patients by each organ, being organ-specific, resulting from the mutual interaction of environmental and genetic factors, including CFTR mutations and various other genes, most of which are associated with inflammatory processes...
March 6, 2018: Current Opinion in Pulmonary Medicine
Laura Fedele, Joseph Newcombe, Maya Topf, Alasdair Gibb, Robert J Harvey, Trevor G Smart
Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg2+ block. In addition, we provide new views on Mg2+ and NMDA channel blocker binding sites...
March 6, 2018: Nature Communications
A M Rose, A Krishan, C F Chakarova, L Moya, S Chambers, M Hollands, J C Illingworth, S M G Williams, H E James, A Z Shah, C N A Palmer, A Chakravarti, J N Berg, J Batra, S S Bhattacharya
Background: MSR1 repeats are a 36-38bp minisatellite element that have recently been implicated in the regulation of gene expression, through copy number variation (CNV). Patients and methods: Bioinformatic and experimental methods were used to assess the distribution of MSR1 across the genome, evaluate the regulatory potential of such elements and explore the role of MSR1 elements in cancer, particularly non-familial breast cancer and prostate cancer. Results: MSR1s are predominately located at chromosome 19 and are functionally enriched in regulatory regions of the genome, particularly regions implicated in short-range regulatory activities (H3K27ac, H3K4me1, and H3K4me3)...
March 2, 2018: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Jingqi Q X Gong, Eric A Sobie
Quantitative mismatches between human physiology and experimental models can be problematic for the development of effective therapeutics. When the effects of drugs on human adult cardiac electrophysiology are of interest, phenotypic differences with animal cells, and more recently stem cell-derived models, can present serious limitations. We addressed this issue through a combination of mechanistic mathematical modeling and statistical analyses. Physiological metrics were simulated in heterogeneous populations of models describing cardiac myocytes from adult ventricles and those derived from induced pluripotent stem cells (iPSC-CMs)...
2018: NPJ Systems Biology and Applications
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