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Ion channel

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
Frederik Flenner, Nicole Arlt, Mahtab Nasib, Sophie Schobesberger, Thea Koch, Ursula Ravens, Felix Friedrich, Viacheslav Nikolaev, Torsten Christ, Sebastian N Stehr
BACKGROUND: Systemic toxicity of local anesthetics is predominantly complicated by their myocardial toxicity. Especially long-acting local anesthetics exert a negative inotropic effect that has been described at lower concentrations than defined for blockade of myocardial ion channels. We evaluated the negative inotropic effect of bupivacaine at a concentration described for clinical toxicity testing the hypothesis that negative inotropy is a result of reduced Ca sensitivity rather than blockade of ion channels...
March 16, 2018: Anesthesiology
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
Ken Matsui, Makoto Ozawa, Maki Kiso, Makoto Yamashita, Toshihiko Maekawa, Minoru Kubota, Sumio Sugano, Yoshihiro Kawaoka
Influenza A viruses cause seasonal epidemics and occasional pandemics. The emergence of viruses resistant to neuraminidase (NA) inhibitors and M2 ion channel inhibitors underlines the need for alternate anti-influenza drugs with novel mechanisms of action. Here, we report the discovery of a host factor as a potential target of anti-influenza drugs. By using cell-based virus replication screening of a chemical library and several additional assays, we identified clonidine as a new anti-influenza agent in vitro...
March 15, 2018: Scientific Reports
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
Ibrahim El-Battrawy, Zhihan Zhao, Huan Lan, Xin Li, Gökhan Yücel, Siegfried Lang, Katherine Sattler, Jan-Dierk Schünemann, Wolfram-Hubertus Zimmermann, Lukas Cyganek, Jochen Utikal, Thomas Wieland, Karen Bieback, Ralf Bauer, Antonius Ratte, Regina Pribe-Wolferts, Kleopatra Rapti, Daniel Nowak, Janina Wittig, Dierk Thomas, Patrick Most, Hugo A Katus, Ursula Ravens, Constanze Schmidt, Martin Borggrefe, Xiao-Bo Zhou, Oliver J Müller, Ibrahim Akin
BACKGROUND: Limb-Girdle muscular dystrophies (LGMD) are a heritable group of genetically determined disorders with a primary involvement of the pelvic or shoulder girdle musculature with partially cardiac manifestation, such as dilated cardiomyopathy (DCM) and life-threatening tachyarrhythmia. We report here that human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes from a patient with LGMD2I and DCM associated with recurrent ventricular tachycardia displayed ion channel dysfunction and abnormality of calcium homeostasis...
March 2018: Circ Genom Precis Med
Gi Young Lee, Deok-Gyun You, Hye-Ra Lee, Sun Wook Hwang, C Justin Lee, Young Do Yoo
Reactive oxygen species (ROS) modulator 1 (Romo1) is a nuclear-encoded mitochondrial inner membrane protein known to regulate mitochondrial ROS production and to act as an essential redox sensor in mitochondrial dynamics. Although its physiological roles have been studied for a decade, the biophysical mechanisms that explain these activities of Romo1 are unclear. In this study, we report that Romo1 is a unique mitochondrial ion channel that differs from currently identified eukaryotic ion channels. Romo1 is a highly conserved protein with structural features of class II viroporins, which are virus-encoded nonselective cation channels...
March 15, 2018: Journal of Cell Biology
Hisao Tsukamoto, Masahiro Higashi, Hideyoshi Motoki, Hiroki Watanabe, Christian Ganser, Koichi Nakajo, Yoshihiro Kubo, Takayuki Uchihashi, Yuji Furutani
Canonical K+ channels are tetrameric and highly K+ selective, whereas two-pore domain K+ (K2P) channels form dimers, but with a similar pore architecture. A two-pore domain potassium channel TWIK1 (KCNK1 or K2P1) allows permeation of Na+ and other monovalent ions, resulting mainly from the presence of Thr118 in the P1 domain. However, the mechanistic basis for this reduced selectivity is unclear. Using ion-exchange-induced difference infrared spectroscopy, we analyzed WT TWIK1 and T118I (highly K+ selective) and L228F (substitution in the P2 domain) TWIK1 variants and found that in the presence of K+ ions, WT and both variants exhibit an amide-I band at 1680 cm-1 This band corresponds to interactions of the backbone carbonyls in the selectivity filter with K+ , a feature very similar to that of the canonical K+ channel KcsA...
March 15, 2018: Journal of Biological Chemistry
Bailin Liu, Ruixiu Shi, Xiang Li, Yanping Liu, Xueqin Feng, Xueyi Chen, Xiaorong Fan, Yingying Zhang, Wenna Zhang, Jiaqi Tang, Xiuwen Zhou, Na Li, Xiyuan Lu, Zhice Xu
BACKGROUND: Prenatal hypoxia is suggested to be associated with increased risks of hypertension in offspring. This study tested whether prenatal hypoxia resulted in salt-sensitive offspring and its related mechanisms of vascular ion channel remodeling. METHODS AND RESULTS: Pregnant rats were housed in a normoxic (21% O2 ) or hypoxic (10.5% O2 ) chamber from gestation days 5 to 21. A subset of male offspring received a high-salt diet (8% NaCl) from 4 to 12 weeks after birth...
March 15, 2018: Journal of the American Heart Association
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
Ekaterina Turlova, Zhong-Ping Feng, Hong-Shuo Sun
Stroke is one of the major causes of mortality and morbidity worldwide, yet novel therapeutic treatments for this condition are lacking. This review focuses on the roles of the transient receptor potential melastatin 2 (TRPM2) ion channels in cellular damage following hypoxia-ischemia and their potential as a future therapeutic target for stroke. Here, we highlight the complex molecular signaling that takes place in neurons, glial cells and the blood-brain barrier following ischemic insult. We also describe the evidence of TRPM2 involvement in these processes, as shown from numerous in vitro and in vivo studies that utilize genetic and pharmacological approaches...
March 15, 2018: Acta Pharmacologica Sinica
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
Justine Marchand, Parisa Heydarizadeh, Benoît Schoefs, Cornelia Spetea
Chloroplasts are endosymbiotic organelles and play crucial roles in energy supply and metabolism of eukaryotic photosynthetic organisms (algae and land plants). They harbor channels and transporters in the envelope and thylakoid membranes, mediating the exchange of ions and metabolites with the cytosol and the chloroplast stroma and between the different chloroplast subcompartments. In secondarily evolved algae, three or four envelope membranes surround the chloroplast, making more complex the exchange of ions and metabolites...
March 14, 2018: Cellular and Molecular Life Sciences: CMLS
Ben Warren, Tom Matheson
Insect auditory receivers provide an excellent comparative resource to understand general principles of auditory transduction, but analysis of the electrophysiological properties of the auditory neurons has been hampered by their tiny size and inaccessibility. Here we pioneer patch-clamp recordings from the auditory neurons of Müller-s Organ of the desert locust Schistocerca gregaria to characterise dendritic spikes, axonal spikes and the transduction current. We demonstrate that dendritic spikes, elicited by sound stimuli, trigger axonal spikes, and that both types are sodium- and voltage-dependent and blocked by TTX...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
John J Marshall, Jian Xu, Anis Contractor
Kainate receptors are members of the glutamate receptor family that function both by generating ionotropic currents through an integral ion channel pore, and through coupling to downstream metabotropic signaling pathways. They are highly expressed in the striatum yet their roles in regulating striatal synapses are not known. Using mice of both sexes we demonstrate that GluK2 containing kainate receptors expressed in direct pathway Spiny Projection Neurons (dSPNs) inhibit glutamate release at corticostriatal synapses in the dorsolateral striatum...
March 14, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
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
Ishan Ghai, Harsha Bajaj, Jayesh Arun Bafna, Hussein Ali El Damrany Hussein, Mathias Winterhalter, Richard Wagner
The outer cell wall of the Gram-negative bacteria is a crucial barrier for antibiotics to reach their target. Here we show that the chemical stability of the widely used antibiotic ampicillin is a major factor in the permeation across OmpF to reach the target in the periplasm. Using planar lipid bilayer we investigated the interactions and permeation of OmpF with ampicillin, its basic pH induced primary degradation product (penicilloic acid), and the chemically more stable benzylpenicillin. We found that the solute induced ion current fluctuation is 10 times higher with penicilloic-acid than with ampicillin...
March 14, 2018: Journal of Biological Chemistry
Ine Vandewauw, Katrien De Clercq, Marie Mulier, Katharina Held, Silvia Pinto, Nele Van Ranst, Andrei Segal, Thierry Voet, Rudi Vennekens, Katharina Zimmermann, Joris Vriens, Thomas Voets
Acute pain represents a crucial alarm signal to protect us from injury. Whereas the nociceptive neurons that convey pain signals were described more than a century ago, the molecular sensors that detect noxious thermal or mechanical insults have yet to be fully identified. Here we show that acute noxious heat sensing in mice depends on a triad of transient receptor potential (TRP) ion channels: TRPM3, TRPV1, and TRPA1. We found that robust somatosensory heat responsiveness at the cellular and behavioural levels is observed only if at least one of these TRP channels is functional...
March 14, 2018: Nature
Victor Matveev
Fundamental cell processes such as synaptic neurotransmitter release, endocrine hormone secretion, and myocyte contraction are controlled by highly localized calcium (Ca2+ ) signals resulting from brief openings of trans-membrane Ca2+ channels. On short temporal and spatial scales, the corresponding local Ca2+ nanodomains formed in the vicinity of a single or several open Ca2+ channels can be effectively approximated by quasi-stationary solutions. The rapid buffering approximation (RBA) is one of the most powerful of such approximations, and is based on the assumption of instantaneous equilibration of the bimolecular Ca2+ buffering reaction, combined with the conservation condition for the total Ca2+ and buffer molecule numbers...
March 13, 2018: Biophysical Journal
Fatimah Alahmari, Bambar Davaasuren, Abdul-Hamid Emwas, Alexander Rothenberger
The new thioaluminogermanate Na(AlS2 )(GeS2 )4 (1) was successfully synthesized by a direct combination reaction. The compound crystallizes in the monoclinic space group P21 / n (no. 14) with unit cell parameters a = 6.803(3) Å, b = 38.207(2) Å, c = 6.947(4) Å, and β = 119.17(3)°. The crystal structure is composed of a [(AlS2 )(GeS2 )4 ]- 3D polyanionic network, in which Al and Ge atoms share the atomic positions and Na cations occupy the channels and voids formed by the connection of (Ge/Al)S4 tetrahedra...
March 14, 2018: Inorganic Chemistry
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