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voltage-gated Na channel

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https://www.readbyqxmd.com/read/28087622/calmodulin-limits-pathogenic-na-channel-persistent-current
#1
Haidun Yan, Chaojian Wang, Steven O Marx, Geoffrey S Pitt
Increased "persistent" current, caused by delayed inactivation, through voltage-gated Na(+) (NaV) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors to these inactivation defects are poorly understood. Here, we show that calmodulin (CaM) binding to multiple sites within NaV channel intracellular C-terminal domains (CTDs) limits persistent Na(+) current and accelerates inactivation across the NaV family. Arrhythmia or epilepsy mutations located in NaV1.5 or NaV1.2 channel CTDs, respectively, reduce CaM binding either directly or by interfering with CTD-CTD interchannel interactions...
January 13, 2017: Journal of General Physiology
https://www.readbyqxmd.com/read/28087597/membrane-depolarizing-channel-blockers-induce-selective-glioma-cell-death-by-impairing-nutrient-transport-and-unfolded-protein-amino-acid-responses
#2
Mia Niklasson, Gianluca Maddalo, Zuzana Sramkova, Ercan Mutlu, Shimei Wee, Petra Sekyrova, Linnéa Schmidt, Nicolas Fritz, Ivar Dehnisch, Gregorios Kyriatzis, Michaela Krafcikova, Brittany B Carson, Jennifer Feenstra, Voichita D Marinescu, Anna Segerman, Martin Haraldsson, Anna-Lena Gustavsson, Lars Gj Hammarström, Annika Jenmalm-Jensen, Lene Uhrbom, A F Maarten Altelaar, Sten Linnarsson, Per Uhlén, Lukas Trantirek, C Theresa Vincent, Sven Nelander, Per Øyvind Enger, Michael Andäng
Glioma-initiating cells (GIC) are considered the underlying cause of recurrences of aggressive glioblastomas, replenishing the tumor population and undermining the efficacy of conventional chemotherapy. Here we report the discovery that inhibiting T-type voltage-gated Ca2+ and KCa channels can effectively induce selective cell death of GIC and increase host survival in an orthotopic mouse model of human glioma. At present, the precise cellular pathways affected by the drugs affecting these channels are unknown...
January 13, 2017: Cancer Research
https://www.readbyqxmd.com/read/28075010/stimulatory-actions-of-a-novel-thiourea-derivative-on-large-conductance-calcium-activated-potassium-channels
#3
Sheng-Nan Wu, Jyh-Haur Chern, Santai Shen, Hwei-Hisen Chen, Ying-Ting Hsu, Chih-Chin Lee, Ming-Huan Chan, Ming-Chi Lai, Feng-Shiun Shie
AIM: In this study, we examine whether an anti-inflammatory thiourea derivative, compound #326, actions on ion channels. METHODS: The effects of compound #326 on Ca(2+) -activated K(+) channels were evaluated by patch-clamp recordings obtained in cell-attached, inside-out or whole-cell configuration. RESULTS: In pituitary GH3 cells, compound #326 increased the amplitude of Ca(2+) -activated K(+) currents (IK(Ca) ) with an EC50 value of 11...
January 11, 2017: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/28074656/atomistic-modeling-of-ion-conduction-through-the-voltage-sensing-domain-of-the-shaker-k-ion-channel
#4
Mona L Wood, J Alfredo Freites, Francesco Tombola, Douglas J Tobias
Voltage-sensing domains (VSDs) are modular membrane protein units that sense changes in the membrane electrostatic potential, and through conformational changes, regulate a specific function. The VSDs of voltage-dependent K+, Na+, and Ca2+ channels do not conduct ions under physiological conditions, but they can become ion-permeable under pathological conditions through mutations in the voltage sensor, particularly of basic residues (mostly arginines) in the S4 helix. Relatively little is known about the underlying mechanisms of conduction through VSDs...
January 11, 2017: Journal of Physical Chemistry. B
https://www.readbyqxmd.com/read/28067623/seizure-control-through-genetic-and-pharmacological-manipulation-of-pumilio-a-key-component-of-neuronal-homeostasis
#5
Wei-Hsiang Lin, Carlo N G Giachello, Richard A Baines
Epilepsy is a significant disorder for which approximately one-third of patients do not respond to drug treatments. Next-generation drugs, which interact with novel targets, are required to provide a better clinical outcome for these individuals. To identify potential novel targets for antiepileptic drug (AED) design, we used RNA sequencing to identify changes in gene transcription in two seizure models of the fruitfly Drosophila melanogaster The first model compared gene transcription between wildtype (WT) and the bangsenseless(1) (para(bss)) mutant; a gain-of-function in the sole fly voltage-gated sodium channel (paralytic)...
December 14, 2016: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28065835/nmr-investigation-of-the-isolated-second-voltage-sensing-domain-of-human-nav1-4-channel
#6
A S Paramonov, E N Lyukmanova, M Yu Myshkin, M A Shulepko, D S Kulbatskii, N S Petrosian, A O Chugunov, D A Dolgikh, M P Kirpichnikov, A S Arseniev, Z O Shenkarev
Voltage-gated Na(+) channels are essential for the functioning of cardiovascular, muscular, and nervous systems. The α-subunit of eukaryotic Na(+) channel consists of ~2000 amino acid residues and encloses 24 transmembrane (TM) helices, which form five membrane domains: four voltage-sensing (VSD) and one pore domain. The structural complexity significantly impedes recombinant production and structural studies of full-sized Na(+) channels. Modular organization of voltage-gated channels gives an idea for studying of the isolated second VSD of human skeletal muscle Nav1...
January 6, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28065753/the-roles-of-conserved-aromatic-residues-tyr5-and-tyr42-in-interaction-of-scorpion-toxin-bmk-agp-sypu1-with-human-nav1-7
#7
Xiangxue Meng, Yijia Xu, Fangyang Wang, Mingyi Zhao, Xue Hou, Yuanyuan Ma, Yao Jin, Yanfeng Liu, Yongbo Song, Jinghai Zhang
Scorpion toxins are invaluable source of therapeutic leads and pharmacological tools which produce influence on the voltage gated sodium channels. In the previous study, our group has reported BmK AGP-SYPU1 (64 amino acids), one scorpion toxin with both potential α-type and β-type scorpion characteristics and analgesic activity in vivo, act as an activator to hNav1.4 and hNav1.5. Additionally, conserved aromatic amino acids Tyr5 and Tyr42 played important roles in bioactivity of BmK AGP-SYPU1 on hNav1.4 and hNav1...
January 5, 2017: International Journal of Biological Macromolecules
https://www.readbyqxmd.com/read/28028533/extracellular-electrical-recording-of-ph-triggered-bursts-in-c6-glioma-cell-populations
#8
Paulo R F Rocha, Maria C R Medeiros, Ulrike Kintzel, Johannes Vogt, Inês M Araújo, Ana L G Mestre, Volker Mailänder, Paul Schlett, Melanie Dröge, Leonid Schneider, Fabio Biscarini, Dago M de Leeuw, Henrique L Gomes
Glioma patients often suffer from epileptic seizures because of the tumor's impact on the brain physiology. Using the rat glioma cell line C6 as a model system, we performed long-term live recordings of the electrical activity of glioma populations in an ultrasensitive detection method. The transducer exploits large-area electrodes that maximize double-layer capacitance, thus increasing the sensitivity. This strategy allowed us to record glioma electrical activity. We show that although glioma cells are nonelectrogenic, they display a remarkable electrical burst activity in time...
December 2016: Science Advances
https://www.readbyqxmd.com/read/28027400/elevated-intracellular-na-concentrations-in-developing-spinal-neurons
#9
Casie Lindsly, Carlos Gonzalez-Islas, Peter Wenner
Over 25 years ago it was first reported that intracellular chloride levels (Cl(-)in ) were higher in developing neurons than in maturity. This finding has had significant implications for understanding the excitability of developing networks and recognizing the underlying causes of hyperexcitability associated with disease and neural injury. While there is some evidence that intracellular sodium levels (Na(+)in ) change during the development of non-neural cells, it has largely been assumed that Na(+)in is the same in developing and mature neurons...
December 27, 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/28024908/hyp-17-a-novel-voltage-gated-sodium-channel-blocker-relieves-inflammatory-and-neuropathic-pain-in-rats
#10
Jee Youn Lee, Yoo Lim Kam, Jungae Oh, Dong Hyun Kim, Jin-Sung Choi, Hae Young Choi, Sungmin Han, Inchan Youn, Hea-Young Park Choo, Tae Young Yune
Clinical and experimental studies suggest that voltage-gated sodium channels (VGSCs) play a key role in the pathogenesis of neuropathic pain and that blocking agents against these channels can be potentially therapeutic. In the current study, we investigated whether a novel compound, (-)-2-Amino-1-(4-((4-chlorophenyl)(phenyl)methyl)piperazin-1-yl)-propan-1-one(HYP-17), binds to VGSCs and evaluated its inhibitory effect on Na(+) currents of the rat dorsal root ganglia (DRG) sensory neurons and its analgesic effect on inflammatory and neuropathic pain...
December 24, 2016: Pharmacology, Biochemistry, and Behavior
https://www.readbyqxmd.com/read/28017670/presynaptic-facilitation-by-tetracaine-of-glutamatergic-spontaneous-excitatory-transmission-in-the-rat-spinal-substantia-gelatinosa-involvement-of-trpa1-channels
#11
Lian-Hua Piao, Tsugumi Fujita, Ting Yu, Eiichi Kumamoto
The amide-type local anesthetic (LA) lidocaine activates transient receptor potential (TRP) ankyrin-1 (TRPA1) channels to facilitate spontaneous L-glutamate release onto spinal substantia gelatinosa (SG) neurons, which play a crucial role in regulating nociceptive transmission. In contrast, the ester-type LA procaine reduces the spontaneous release of L-glutamate in SG neurons. In order to determine whether TRPA1 activation by LAs is specific to amide-types, we examined the actions of tetracaine, another ester-type LA, and other amide-type LAs on glutamatergic spontaneous excitatory transmission in SG neurons by focusing on TRP activation...
December 22, 2016: Brain Research
https://www.readbyqxmd.com/read/28012039/characterization-of-specific-allosteric-effects-of-the-na-channel-%C3%AE-1-subunit-on-the-nav1-4-isoform
#12
Alfredo Sánchez-Solano, Angel A Islas, Thomas Scior, Bertin Paiz-Candia, Lourdes Millan-PerezPeña, Eduardo M Salinas-Stefanon
The mechanism of inactivation of mammalian voltage-gated Na(+) channels involves transient interactions between intracellular domains resulting in direct pore occlusion by the IFM motif and concomitant extracellular interactions with the β1 subunit. Navβ1 subunits constitute single-pass transmembrane proteins that form protein-protein associations with pore-forming α subunits to allosterically modulate the Na(+) influx into the cell during the action potential of every excitable cell in vertebrates. Here, we explored the role of the intracellular IFM motif of rNav1...
December 23, 2016: European Biophysics Journal: EBJ
https://www.readbyqxmd.com/read/27999941/extracellular-phosphates-enhance-activities-of-voltage-gated-proton-channels-and-production-of-reactive-oxygen-species-in-murine-osteoclast-like-cells
#13
Guangshuai Li, Katsuyuki Miura, Miyuki Kuno
Osteoclasts are highly differentiated bone-resorbing cells and play a significant role in bone remodelling. In the resorption pit, inorganic phosphate (Pi) concentrations increase because of degradation of hydroxyapatite. We studied effects of extracellular Pi on voltage-gated H(+) channels in osteoclast-like cells derived from a macrophage cell line (RAW264). Extracellular Pi (1.25-20 mM) increased the H(+) channel currents dose dependently and reversibly. The Pi-induced increases were attenuated by removal of extracellular Na(+) and by phosphonoformic acid, a blocker of Na(+)-dependent Pi transporters...
December 21, 2016: Pflügers Archiv: European Journal of Physiology
https://www.readbyqxmd.com/read/27998617/biophysical-molecular-and-pharmacological-characterization-of-voltage-dependent-sodium-channels-from-induced-pluripotent-stem-cell-derived-cardiomyocytes
#14
Adrien Moreau, Aurélie Mercier, Olivier Thériault, Mohamed Boutjdir, Bettina Burger, Dagmar I Keller, Mohamed Chahine
BACKGROUND: The ability to differentiate patient-specific human induced pluripotent stem cells in cardiac myocytes (hiPSC-CM) offers novel perspectives for cardiovascular research. A number of studies, that reported mainly on current-voltage curves used hiPSC-CM to model voltage-gated Na(+) channel (Nav) dysfunction. However, the expression patterns and precise biophysical and pharmacological properties of Nav channels from hiPSC-CM remain unknown. Our objective was to study the characteristics of Nav channels from hiPSC-CM and assess the appropriateness of this novel cell model...
October 11, 2016: Canadian Journal of Cardiology
https://www.readbyqxmd.com/read/27990272/evaluation-of-recombinant-monoclonal-antibody-svmab1-binding-to-na-v1-7-target-sequences-and-block-of-human-na-v1-7-currents
#15
Dong Liu, Mandy Tseng, Linda F Epstein, Lydia Green, Brian Chan, Brian Soriano, Desiree Lim, Oscar Pan, Christopher M Murawsky, Chadwick T King, Bryan D Moyer
Identification of small and large molecule pain therapeutics that target the genetically validated voltage-gated sodium channel Na V1.7 is a challenging endeavor under vigorous pursuit. The monoclonal antibody SVmab1 was recently published to bind the Na V1.7 DII voltage sensor domain and block human Na V1.7 sodium currents in heterologous cells. We produced purified SVmab1 protein based on publically available sequence information, and evaluated its activity in a battery of binding and functional assays. Herein, we report that our recombinant SVmAb1 does not bind peptide immunogen or purified Na V1...
2016: F1000Research
https://www.readbyqxmd.com/read/27988317/nonequilibrium-response-of-a-voltage-gated-sodium-ion-channel-and-biophysical-characterization-of-dynamic-hysteresis
#16
Krishnendu Pal, Biswajit Das, Gautam Gangopadhyay
Here we have studied the dynamic as well as the non-equilibrium thermodynamic response properties of voltage-gated Na-ion channel. Using sinusoidally oscillating external voltage protocol we have both kinetically and energetically studied the non-equilibrium steady state properties of dynamic hysteresis in details. We have introduced a method of estimating the work done associated with the dynamic memory due to a cycle of oscillating voltage. We have quantitatively characterised the loop area of ionic current which gives information about the work done to sustain the dynamic memory only for ion conduction, while the loop area of total entropy production rate gives the estimate of work done for overall gating dynamics...
December 14, 2016: Journal of Theoretical Biology
https://www.readbyqxmd.com/read/27984177/hydrogen-sulfide-inhibits-giant-depolarizing-potentials-and-abolishes-epileptiform-activity-of-neonatal-rat-hippocampal-slices
#17
Aleksey V Yakovlev, Evgeniya D Kurmasheva, Rashid Giniatullin, Ilgam Khalilov, Guzel F Sitdikova
Hydrogen sulfide (H2S) is an endogenous gasotransmitter with neuroprotective properties that participates in the regulation of transmitter release and neuronal excitability in various brain structures. The role of H2S in the growth and maturation of neural networks however remains unclear. The aim of the present study is to reveal the effects of H2S on neuronal spontaneous activity relevant to neuronal maturation in hippocampal slices of neonatal rats. Sodium hydrosulfide (NaHS) (100 μM), a classical donor of H2S produced a biphasic effect with initial activation and subsequent concentration-dependent suppression of network-driven giant depolarizing potentials (GDPs) and neuronal spiking activity...
October 27, 2016: Neuroscience
https://www.readbyqxmd.com/read/27983579/what-ion-flow-along-ion-channels-can-tell-us-about-their-functional-activity
#18
REVIEW
Lucia Becucci, Rolando Guidelli
The functional activity of channel-forming peptides and proteins is most directly verified by monitoring the flow of physiologically relevant inorganic ions, such as Na⁺, K⁺ and Cl(-), along the ion channels. Electrical current measurements across bilayer lipid membranes (BLMs) interposed between two aqueous solutions have been widely employed to this end and are still extensively used. However, a major drawback of BLMs is their fragility, high sensitivity toward vibrations and mechanical shocks, and low resistance to electric fields...
December 13, 2016: Membranes
https://www.readbyqxmd.com/read/27966485/metabolic-alterations-derived-from-absence-of-two-pore-channel-1-at-cardiac-level
#19
Vanessa Garcia-Rua, Sandra Feijoo-Bandin, Maria Garcia-Vence, Alana Aragon-Herrera, Susana B Bravo, Diego Rodriguez-Penas, Ana Mosquera-Leal, Pamela V Lear, John Parrington, Jana Alonso, Esther Rosello-Lleti, Manuel Portoles, Miguel Rivera, Jose Ramon Gonzalez-Juanatey, Francisca Lago
Two-pore channels (TPCs or TPCNs) are novel voltage-gated ion channels that have been postulated to act as Ca2+ and/or Na+ channels expressed exclusively in acidic organelles such as endosomes and lysosomes. TPCNs participate in the regulation of diverse biological processes and recently have been proposed to be involved in the pathophysiology of metabolic disorders such as obesity, fatty liver disease and type 2 diabetes mellitus. Due to the importance of these pathologies in the development of cardiovascular diseases, we aimed to study the possible role of two-pore channel 1 (TPCN1) in the regulation of cardiac metabolism...
December 2016: Journal of Biosciences
https://www.readbyqxmd.com/read/27941820/isolated-pores-dissected-from-human-two-pore-channel-2-are-functional
#20
Christopher J Penny, Taufiq Rahman, Altin Sula, Andrew J Miles, B A Wallace, Sandip Patel
Multi-domain voltage-gated ion channels appear to have evolved through sequential rounds of intragenic duplication from a primordial one-domain precursor. Whereas modularity within one-domain symmetrical channels is established, little is known about the roles of individual regions within more complex asymmetrical channels where the domains have undergone substantial divergence. Here we isolated and characterised both of the divergent pore regions from human TPC2, a two-domain channel that holds a key intermediate position in the evolution of voltage-gated ion channels...
December 12, 2016: Scientific Reports
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