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https://www.readbyqxmd.com/read/28335032/allele-specific-ablation-rescues-electrophysiological-abnormalities-in-a-human-ips-cell-model-of-long-qt-syndrome-with-a-calm2-mutation
#1
Yuta Yamamoto, Takeru Makiyama, Takeshi Harita, Kenichi Sasaki, Yimin Wuriyanghai, Mamoru Hayano, Suguru Nishiuchi, Hirohiko Kohjitani, Sayako Hirose, Jiarong Chen, Fumika Yokoi, Taisuke Ishikawa, Seiko Ohno, Kazuhisa Chonabayashi, Hideki Motomura, Yoshinori Yoshida, Minoru Horie, Naomasa Makita, Takeshi Kimura
Background: Calmodulin is a ubiquitous Ca 2+ sensor molecule encoded by three distinct calmodulin genes, CALM1-3 . Recently, mutations in CALM1-3 have been reported to be associated with severe early-onset long-QT syndrome (LQTS). However, the underlying mechanism through which heterozygous calmodulin mutations lead to severe LQTS remains unknown, particularly in human cardiomyocytes. Objectives: We aimed to establish an LQTS disease model associated with a CALM2 mutation (LQT15) using human induced pluripotent stem cells (hiPSCs) and to assess mutant allele-specific ablation by genome editing for the treatment of LQT15...
March 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28334404/calcium-homeostasis-modulator-1-like-currents-in-rat-fungiform-taste-cells-expressing-amiloride-sensitive-sodium-currents
#2
Albertino Bigiani
Salt reception by taste cells is still the less understood transduction process occurring in taste buds, the peripheral sensory organs for the detection of food chemicals. Although there is evidence suggesting that the epithelial sodium channel (ENaC) works as sodium receptor, yet it is not clear how salt-detecting cells signal the relevant information to nerve endings. Taste cells responding to sweet, bitter, and umami substances release ATP as neurotransmitter through a nonvesicular mechanism. Three different channel proteins have been proposed as conduit for ATP secretion: pannexin channels, connexin hemichannels, and calcium homeostasis modulator 1 (CALHM1) channels...
March 10, 2017: Chemical Senses
https://www.readbyqxmd.com/read/28334184/mild-traumatic-brain-injury-induces-structural-and-functional-disconnection-of-local-neocortical-inhibitory-networks-via-parvalbumin-interneuron-diffuse-axonal-injury
#3
Michal Vascak, Xiaotao Jin, Kimberle M Jacobs, John T Povlishock
Diffuse axonal injury (DAI) plays a major role in cortical network dysfunction posited to cause excitatory/inhibitory imbalance after mild traumatic brain injury (mTBI). Current thought holds that white matter (WM) is uniquely vulnerable to DAI. However, clinically diagnosed mTBI is not always associated with WM DAI. This suggests an undetected neocortical pathophysiology, implicating GABAergic interneurons. To evaluate this possibility, we used mild central fluid percussion injury to generate DAI in mice with Cre-driven tdTomato labeling of parvalbumin (PV) interneurons...
March 4, 2017: Cerebral Cortex
https://www.readbyqxmd.com/read/28333338/drug-discovery-for-male-subfertility-using-high-throughput-screening-a-new-approach-to-an-unsolved-problem
#4
Sarah J Martins da Silva, Sean G Brown, Keith Sutton, Louise V King, Halil Ruso, David W Gray, Paul G Wyatt, Mark C Kelly, Christopher L R Barratt, Anthony G Hope
STUDY QUESTION: Can pharma drug discovery approaches be utilized to transform investigation into novel therapeutics for male infertility? SUMMARY ANSWER: High-throughput screening (HTS) is a viable approach to much-needed drug discovery for male factor infertility. WHAT IS KNOWN ALREADY: There is both huge demand and a genuine clinical need for new treatment options for infertile men. However, the time, effort and resources required for drug discovery are currently exorbitant, due to the unique challenges of the cellular, physical and functional properties of human spermatozoa and a lack of appropriate assay platform...
March 16, 2017: Human Reproduction
https://www.readbyqxmd.com/read/28331977/role-of-plasma-membrane-associated-akaps-for-the-regulation-of-cardiac-ik1-current-by-protein-kinase-a
#5
Claudia Seyler, Daniel Scherer, Christoph Köpple, Martin Kulzer, Sevil Korkmaz, Panagiotis Xynogalos, Dierk Thomas, Ziya Kaya, Eberhard Scholz, Johannes Backs, Christoph Karle, Hugo A Katus, Edgar Zitron
The cardiac IK1 current stabilizes the resting membrane potential of cardiomyocytes. Protein kinase A (PKA) induces an inhibition of IK1 current which strongly promotes focal arrhythmogenesis. The molecular mechanisms underlying this regulation have only partially been elucidated yet. Furthermore, the role of A-kinase anchoring proteins (AKAPs) in this regulation has not been examined to date. The objective of this project was to elucidate the molecular mechanisms underlying the inhibition of IK1 by PKA and to identify novel molecular targets for antiarrhythmic therapy downstream β-adrenoreceptors...
March 22, 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
https://www.readbyqxmd.com/read/28331181/multi-walled-carbon-nanotubes-act-as-a-chemokine-and-recruit-macrophages-by-activating-the-plc-ip3-crac-channel-signaling-pathway
#6
Hui Li, Xiao-Qiu Tan, Li Yan, Bo Zeng, Jie Meng, Hai-Yan Xu, Ji-Min Cao
The impact of nanomaterials on immune cells is gaining attention but is not well documented. Here, we report a novel stimulating effect of carboxylated multi-walled carbon nanotubes (c-MWCNTs) on the migration of macrophages and uncover the underlying mechanisms, especially the upstream signaling, using a series of techniques including transwell migration assay, patch clamp, ELISA and confocal microscopy. c-MWCNTs dramatically stimulated the migration of RAW264.7 macrophages when endocytosed, and this effect was abolished by inhibiting phospholipase C (PLC) with U-73122, antagonizing the IP3 receptor with 2-APB, and blocking calcium release-activated calcium (CRAC) channels with SK&F96365...
March 22, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28327344/direct-activation-of-ca-2-and-voltage-gated-potassium-channels-of-large-conductance-by-anandamide-in-endothelial-cells-does-not-support-the-presence-of-endothelial-atypical-cannabinoid-receptor
#7
Alexander I Bondarenko, Olga Panasiuk, Iryna Okhai, Fabrizio Montecucco, Karim J Brandt, Francois Mach
Endocannabinoid anandamide induces endothelium-dependent relaxation commonly attributed to stimulation of the G-protein coupled endothelial anandamide receptor. The study addressed the receptor-independent effect of anandamide on large conductance Ca(2+)-dependent K(+) channels expressed in endothelial cell line EA.hy926. Under resting conditions, 10µM anandamide did not significantly influence the resting membrane potential. In a Ca(2+)-free solution the cells were depolarized by ~10 mV. Further administration of 10µM anandamide hyperpolarized the cells by ~8 mV...
March 19, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28327076/myocardial-protection-during-minimally-invasive-cardiac-surgery-through-right-mini-thoracotomy
#8
Micaela De Palo, Pietro Guida, Florinda Mastro, Daniela Nanna, Teresa A P Quagliara, Ruggiero Rociola, Giosuè Lionetti, Domenico Paparella
BACKGROUND: Myocardial damage is an independent predictor of adverse outcome following cardiac surgery and myocardial protection is one of the key factors to achieve successful outcomes. Cardioplegia with Custodiol is currently the most used cardioplegia during minimally invasive cardiac surgery (MICS). Different randomized controlled trials compared blood and Custodiol cardioplegia in the context of traditional cardiac surgery. No data are available for MICS. AIM: The aim of this study was to compare the efficacy of cold blood versus Custodiol cardioplegia during MICS...
April 2017: Perfusion
https://www.readbyqxmd.com/read/28326934/activations-of-muscarinic-m1-receptors-in-the-anterior-cingulate-cortex-contribute-to-the-antinociceptive-effect-via-gabaergic-transmission
#9
Kohei Koga, Yu Matsuzaki, Kenji Honda, Fumihiro Eto, Tomonori Furukawa, Keisuke Migita, Keiichi Irie, Kenichi Mishima, Shinya Ueno
Background Cholinergic systems regulate the synaptic transmission resulting in the contribution of the nociceptive behaviors. Anterior cingulate cortex is a key cortical area to play roles in nociception and chronic pain. However, the effect of the activation of cholinergic system for nociception is still unknown in the cortical area. Here, we tested whether the activation of cholinergic receptors can regulate nociceptive behaviors in adult rat anterior cingulate cortex by integrative methods including behavior, immunohistochemical, and electrophysiological methods...
January 2017: Molecular Pain
https://www.readbyqxmd.com/read/28325748/halogenated-ether-alcohol-and-alkane-anesthetics-activate-task-3-tandem-pore-potassium-channels-likely-through-a-common-mechanism
#10
Anita Luethy, James D Boghosian, Rithu Srikantha, Joseph Cotten
TASK-3 (KCNK9) tandem pore potassium channel function is activated by halogenated anesthetics through binding at a putative anesthetic binding cavity. To understand pharmacological requirements for TASK-3 activation, we studied the concentration-response of TASK-3 to several anesthetics (isoflurane, desflurane, sevoflurane, halothane, α-chloralose, 2,2,2-trichloroethanol(TCE), and chloral hydrate), to ethanol, and to a panel of halogenated methanes and alcohols. We used mutagenesis to probe the anesthetic binding cavity as observed in a TASK-3 homology model...
March 21, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28322838/effect-of-antiarrhythmic-drugs-on-small-conductance-calcium-activated-potassium-channels
#11
Rafel Simó Vicens, Daniel R P Sauter, Morten Grunnet, Jonas G Diness, Bo H Bentzen
Atrial fibrillation (AF) is the most common type of arrhythmia. Current pharmacological treatment for AF is moderately effective and/or increases the risk of serious ventricular adverse effects. To avoid ventricular adverse effects, a new target has been considered, the small conductance calcium-activated K(+) channels (KCa2.X, SK channels). In the heart, KCa2.X channels are functionally more important in atria compared to ventricles, and pharmacological inhibition of the channel confers atrial selective prolongation of the cardiac action potential and converts AF to sinus rhythm in animal models of AF...
March 18, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28322832/dapoxetine-induces-neuroprotective-effects-against-glutamate-induced-neuronal-cell-death-by-inhibiting-calcium-signaling-and-mitochondrial-depolarization-in-cultured-rat-hippocampal-neurons
#12
Imju Jeong, Ji Seon Yang, Yi Jae Hong, Hee Jung Kim, Sang June Hahn, Shin Hee Yoon
Selective serotonin reuptake inhibitors (SSRIs) have an inhibitory effect on various ion channels including Ca(2+) channels. We used fluorescent dye-based digital imaging, whole-cell patch clamping and cytotoxicity assays to examine whether dapoxetine, a novel rapid-acting SSRI, affect glutamate-induced calcium signaling, mitochondrial depolarization and neuronal cell death in cultured rat hippocampal neurons. Pretreatment with dapoxetine for 10min inhibited glutamate-induced intracellular free Ca(2+) concentration ([Ca(2+)]i) increases in a concentration-dependent manner (Half maximal inhibitory concentration= 4...
March 16, 2017: European Journal of Pharmacology
https://www.readbyqxmd.com/read/28322303/a-new-electro-optical-approach-for-conductance-measurement-an-assay-for-the-study-of-drugs-acting-on-ligand-gated-ion-channels
#13
A Menegon, S Pitassi, N Mazzocchi, L Redaelli, R Rizzetto, J F Rolland, C Poli, M Imberti, A Lanati, F Grohovaz
Ligand gated ion channels are involved in many pathophysiological processes and represent a relevant, although challenging, target for drug discovery. We propose an innovative electro-optical approach to their analysis able to derive membrane conductance values from the local membrane potential changes imposed by test current pulses and measured by fast voltage-sensitive fluorescent dyes. We exploited the potential of this proprietary method by developing a drug testing system called "ionChannel Optical High-content Microscope" (ionChannelΩ)...
March 21, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28320963/conformational-dynamics-and-role-of-the-acidic-pocket-in-asic-ph-dependent-gating
#14
Sabrina Vullo, Gaetano Bonifacio, Sophie Roy, Niklaus Johner, Simon Bernèche, Stephan Kellenberger
Acid-sensing ion channels (ASICs) are proton-activated Na(+) channels expressed in the nervous system, where they are involved in learning, fear behaviors, neurodegeneration, and pain sensation. In this work, we study the role in pH sensing of two regions of the ectodomain enriched in acidic residues: the acidic pocket, which faces the outside of the protein and is the binding site of several animal toxins, and the palm, a central channel domain. Using voltage clamp fluorometry, we find that the acidic pocket undergoes conformational changes during both activation and desensitization...
March 20, 2017: Proceedings of the National Academy of Sciences of the United States of America
https://www.readbyqxmd.com/read/28320841/prefrontal-cortex-kca2-channels-regulate-mglu5-dependent-plasticity-and-extinction-of-alcohol-seeking-behavior
#15
Reginald Cannady, Justin T McGonigal, Ryan J Newsom, John J Woodward, Patrick J Mulholland, Justin T Gass
Identifying novel treatments that facilitate extinction learning could enhance cue-exposure therapy and reduce high relapse rates in alcoholics. Activation of mGlu5 receptors in the infralimbic prefrontal cortex (IL-PFC) facilitates learning during extinction of cue-conditioned alcohol-seeking behavior. Small-conductance calcium-activated potassium (KCa2) channels have also been implicated in extinction learning of fear memories, and mGlu5 receptor activation can reduce KCa2 channel function. Using a combination of electrophysiological, pharmacological, and behavioral approaches, this study examined KCa2 channels as a novel target to facilitate extinction of alcohol-seeking behavior in rats...
March 20, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28320163/inhibition-of-17-beta-estradiol-on-neuronal-excitability-via-enhancing-girk1-mediated-inwardly-rectifying-potassium-currents-and-girk1-expression
#16
Yuwen Zhang, Yian Huang, Guoxiang Wang, Xin Wang, Yun Wang
BACKGROUND: Catamenial epilepsy is a common central nervous system disease in female, which is influenced by the 17-β-estradiol (estrogen) level during the menstrual cycle. Low level (<0.05ng/ml) of estrogen normally accompanies with the perimenstrual classification of catamenial epilepsy, however, without clear mechanism. In previous studies, estrogen has been demonstrated to possess widely regulatory effects on potassium channels. Here, the effect of 17-β-estradiol on modulating inwardly rectifying K(+) (Kir) currents was investigated in cultured hippocampal neurons...
April 15, 2017: Journal of the Neurological Sciences
https://www.readbyqxmd.com/read/28319196/h-channels-in-embryonic-biomphalaria-glabrata-cell-membranes-putative-roles-in-snail-host-schistosome-interactions
#17
Brandon J Wright, Utibe Bickham-Wright, Timothy P Yoshino, Meyer B Jackson
The human blood fluke Schistosoma mansoni causes intestinal schistosomiasis, a widespread neglected tropical disease. Infection of freshwater snails Biomphalaria spp. is an essential step in the transmission of S. mansoni to humans, although the physiological interactions between the parasite and its obligate snail host that determine success or failure are still poorly understood. In the present study, the B. glabrata embryonic (Bge) cell line, a widely used in vitro model for hemocyte-like activity, was used to investigate membrane properties, and assess the impact of larval transformation proteins (LTP) on identified ion channels...
March 20, 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28315292/hypoxic-culture-promotes-dopaminergic-neuronal-differentiation-of-nasal-olfactory-mucosa-mesenchymal-stem-cells-via-up-regulation-of-hypoxia-inducible-factor-1%C3%AE
#18
Yi Zhuo, Lei Wang, Lite Ge, Xuan Li, Ping Chen, Da Duan, Xiaohua Teng, Miao Jiang, Kai Liu, Ting Yuan, Pei Wu, Hao Wang, Yujia Deng, Huali Xie, Ying Xia, Ming Lu
<p><b>Background</b> Olfactory mucosa mesenchymal stem cells (OM-MSCs) display significant clonogenicactivity and may be easily propagated for Parkinson's disease therapies. Methods of inducing OM-MSCs to differentiate into dopaminergic (DAergic) neurons using olfactory ensheathing cells (OECs) is thus an attractive topic of research.</p><p><b>Methods</b> We designed a hypoxic-induction protocol to generate DAergic neurons from OM-MSCs using a physiological oxygen (O2) level of 3% and OEC-conditioned medium (HI group)...
March 17, 2017: Cell Transplantation
https://www.readbyqxmd.com/read/28314951/relaxin-3-rxfp3-signalling-in-mouse-hypothalamus-no-effect-of-rxfp3-activation-on-corticosterone-despite-reduced-presynaptic-excitatory-input-onto-paraventricular-crh-neurons-in-vitro
#19
C Zhang, D V Baimoukhametova, C M Smith, J S Bains, Andrew L Gundlach
Relaxin-3/RXFP3 signalling is proposed to be involved in the neuromodulatory control of arousal- and stress-related neural circuits. Furthermore, previous studies in rats have led to the proposal that relaxin-3/RXFP3 signalling is associated with activation of the hypothalamic-pituitary-adrenal axis, but direct evidence for RXFP3-related actions on the activity of hypothalamic corticotropin-releasing hormone (CRH) neurons is lacking. In this study, we investigated characteristics of the relaxin-3/RXFP3 system in mouse hypothalamus...
March 17, 2017: Psychopharmacology
https://www.readbyqxmd.com/read/28306530/ascorbic-acid-does-not-modulate-potassium-currents-in-cultured-human-lymphocytes
#20
Saravanakumar Snekalatha, Praghalathan Kanthakumar
BACKGROUND: Ascorbic acid (AA) is known to modulate lymphocyte function, but the mechanism of action is not clearly understood. As voltage-gated potassium currents play an important role in lymphocyte function, the effect of AA on voltage-gated potassium currents was studied. METHODS: Peripheral blood mononuclear cells were cultured in the presence of increasing concentrations of AA (0, 0.125, 0.25, 0.5, and 1 mM). Potassium currents in resting lymphocytes were studied by whole cell patch clamp technique using a depolarizing protocol...
March 17, 2017: Journal of Basic and Clinical Physiology and Pharmacology
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