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voltage-gated Na channel

Martin Loynaz Prieto, Kamyar Firouzi, Butrus T Khuri-Yakub, Merritt Maduke
Ultrasound (US) can modulate the electrical activity of the excitable tissues, but the mechanisms underlying this effect are not understood at the molecular level or in terms of the physical modality through which US exerts its effects. Here, we report an experimental system that allows for stable patch-clamp recording in the presence of US at 43 MHz, a frequency known to stimulate neural activity. We describe the effects of US on two ion channels proposed to be involved in the response of excitable cells to US: the mechanosensitive Piezo1 channel and the voltage-gated sodium channel NaV 1...
March 7, 2018: Ultrasound in Medicine & Biology
Csaba Fekete, Csaba Vastagh, Ádám Dénes, Erik Hrabovszky, Gábor Nyiri, Imre Kalló, Zsolt Liposits, Miklós Sárvári
Microglia are instrumental for recognition and elimination of amyloid β1-42 oligomers (AβO), but the long-term consequences of AβO-induced inflammatory changes in the brain are unclear. Here, we explored microglial responses and transciptome-level inflammatory signatures in the rat hippocampus after chronic AβO challenge. Middle-aged Long Evans rats received intracerebroventricular infusion of AβO or vehicle for 4 weeks, followed by treatment with artificial CSF or MCC950 for the subsequent 4 weeks. AβO infusion evoked a sustained inflammatory response including activation of NF-κB, triggered microglia activation and increased the expression of pattern recognition and phagocytic receptors...
March 6, 2018: Neuroscience
Qingjuan Hu, Yuping Li, Chao Liu, Li-Ping Huang, Lvming Zeng, Songhua Wang, Hao Song, Hailong Peng, Jianhua Huang, Chong Chen, Li-Hua Yao
Our previous work showed that polysaccharide isolated from Portulaca oleracea L. (POP) has an insulinotropic effect. The voltage-gated Na+ channel (VGSC) in the excitement phase plays an important role. This work aims to study the effect of POP on the voltage-gated Na+ channel current (INa ) and its channel dynamic characteristics in insulin-secreting β-cell line (INS-1) cells of rat. Our results revealed that POP can inhibit the amplitude of INa and improve cell survival in a concentration-dependent manner...
March 4, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Stephanie Hartmann, Fang Zheng, Michele Constanze Kyncl, Sandra Karch, Kerstin Voelkl, Benedikt Zott, Carla D'Avanzo, Selene Lomoio, Giuseppina Tesco, Doo Yeon Kim, Christian Alzheimer, Tobias Huth
β-Secretase BACE1 is deemed a major culprit in Alzheimer's disease, but accumulating evidence indicates that there is more to the enzyme than driving the amyloidogenic processing of the amyloid precursor protein. For example, BACE1 has emerged as an important regulator of neuronal activity through proteolytic and, most unexpectedly, also through non-proteolytic interactions with several ion channels. Here, we identify and characterize the voltage-gated K+ channel 3.4 as a new and functionally relevant interaction partner of BACE1...
March 5, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Dongfang Tang, Zhen Xiao, Yan Xu, Jiao Zeng, Dezheng Peng, Songping Liang, Cheng Tang, Zhonghua Liu
Spider venom is rich in peptide toxins that could be used to explore the structure and function of voltage-gated sodium channels (NaV s). This study has characterized a 44-amino acid peptide toxin, δ-hexatoxin-MrIX (δ-HXTX-MrIX), from the venom of the spider Macrothele raveni. δ-hexatoxin-MrIX potently inhibited the fast inactivation of NaV s in mouse cerebellar granule cells (CGCs) with an EC50 of 35.3 ± 5.9 nM. The toxin shifted both the steady-state activation and the steady-state inactivation curves of CGC NaV s to the hyperpolarized direction...
February 28, 2018: Peptides
Sascha R A Alles, Peter A Smith
Injury to or disease of the nervous system can invoke chronic and sometimes intractable neuropathic pain. Many parallel, interdependent, and time-dependent processes, including neuroimmune interactions at the peripheral, supraspinal, and spinal levels, contribute to the etiology of this "disease of pain." Recent work emphasizes the roles of colony-stimulating factor 1, ATP, and brain-derived neurotrophic factor. Excitatory processes are enhanced, and inhibitory processes are attenuated in the spinal dorsal horn and throughout the somatosensory system...
April 2018: Pharmacological Reviews
Lubin Chen, Jianying Huang, Peng Zhao, Anna-Karin Persson, Fadia B Dib-Hajj, Xiaoyang Cheng, Andrew Tan, Stephen G Waxman, Sulayman D Dib-Hajj
Voltage-gated sodium channels NaV 1.7, NaV 1.8 and NaV 1.9 have been the focus for pain studies because their mutations are associated with human pain disorders, but the role of NaV 1.6 in pain is less understood. In this study, we selectively knocked out NaV 1.6 in dorsal root ganglion (DRG) neurons, using NaV 1.8-Cre directed or adeno-associated virus (AAV)-Cre mediated approaches, and examined the specific contribution of NaV 1.6 to the tetrodotoxin-sensitive (TTX-S) current in these neurons and its role in neuropathic pain...
March 1, 2018: Scientific Reports
Jia-Zeng Wang, Rui-Zhen Wang
Potassium channels mainly contribute to the resting potential and re-polarizations, with the potassium electrochemical gradient being maintained by the pump Na+ /K+ -ATPase. In this paper, we construct a stochastic model mimicking the kinetics of a potassium channel, which integrates temporal evolving of the membrane voltage and the spontaneous gating of the channel. Its stationary probability density functions (PDFs) are found to be singular at the boundaries, which result from the fact that the evolving rates of voltage are greater than the gating rates of the channel...
February 2018: Chaos
Lin Zhou, Liang Zhou, Li-da Su, Sheng-Long Cao, Ya-Jun Xie, Na Wang, Chong-Yu Shao, Ya-Nan Wang, Jia-Huan Zhou, John K Cowell, Ying Shen
Autosomal dominant lateral temporal epilepsy (ADLTE) is an inherited syndrome caused by mutations in the leucine-rich glioma inactivated 1 (LGI1) gene. It is known that glutamatergic transmission is altered in LGI1 mutant mice and seizures can be reduced by restoring LGI1 function. Yet, the mechanism underlying ADLTE is unclear. Here, we propose that seizures in male LGI1-/- mice are due to non-synaptic epileptiform activity in cortical neurons. We examined the intrinsic excitability of pyramidal neurons in the temporal cortex of male LGI1-/- mice and found that the voltage-gated K+ channel Kv1...
February 28, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Edmund Cheung So, Yingwei Wang, Li Qun Yang, Kenny Hsu So, Yi-Ching Lo, Sheng-Nan Wu
GMQ (2-guanidine-4-methylquinazoline or N-(4-methyl-2-quinazolinyl)-guanidine hydrochloride), an agonist of acid-sensing ion channel type 3, has been increasingly used for in vivo studies of alternations in nociceptic behavior. In this study, we tried to investigate whether GMQ has any possible effect on other types of ion channels. Addition of GMQ to pituitary GH3 cells raised the amplitude of Ca2+ -activated K+ currents (IK(Ca) ), which was reversed by verruculogen or PF1022A, but not by TRAM-39. Under inside-out current recordings, addition of GMQ into bath enhanced the probability of large-conductance Ca2+ -activated K+ (BKCa ) channels with an EC50 value of 0...
February 22, 2018: Biochemical Pharmacology
Tânia C Gonçalves, Rachid Boukaiba, Jordi Molgó, Muriel Amar, Michel Partiseti, Denis Servent, Evelyne Benoit
The Chinese bird spider huwentoxin-IV (HwTx-IV) is well-known to be a highly potent blocker of NaV 1.7 subtype of voltage-gated sodium (NaV ) channels, a genetically validated analgesic target, and thus promising as a potential lead molecule for the development of novel pain therapeutics. In the present study, the interaction between HwTx-IV and NaV 1.6 channel subtype was investigated using multiscale (from in vivo to individual cell) functional approaches. HwTx-IV was approximatively 2 times more efficient than tetrodotoxin (TTX) to inhibit the compound muscle action potential recorded from the mouse skeletal neuromuscular system in vivo, and 30 times more effective to inhibit nerve-evoked than directly-elicited muscle contractile force of isolated mouse hemidiaphragms...
February 20, 2018: Neuropharmacology
Mónica Rubio Ayala, Tatiana Syrovets, Susanne Hafner, Vitalii Zablotskii, Alexandr Dejneka, Thomas Simmet
Cellular function is modulated by the electric membrane potential controlling intracellular physiology and signal propagation from a motor neuron to a muscle fiber resulting in muscle contraction. Unlike electric fields, magnetic fields are not attenuated by biological materials and penetrate deep into the tissue. We used complex spatiotemporal magnetic fields (17-70 mT) to control intracellular signaling in skeletal muscle cells. By changing different parameters of the alternating magnetic field (amplitude, inversion time, rotation frequency), we induced transient depolarization of cellular membranes leading to i) Na+ influx through voltage-gated sodium channels (VGSC), ii) cytosolic calcium increase, and iii) VGSC- and ryanodine receptor-dependent increase of actin polymerization...
February 16, 2018: Biomaterials
Tariq Zaman, Ingo Helbig, Ivana Babić Božović, Suzanne D DeBrosse, A Christina Bergqvist, Kimberly Wallis, Livija Medne, Aleš Maver, Borut Peterlin, Katherine L Helbig, Xiaohong Zhang, Ethan M Goldberg
OBJECTIVE: Voltage-gated sodium (Na+ ) channels underlie action potential generation and propagation and hence are central to the regulation of excitability in the nervous system. Mutations in the genes SCN1A, SCN2A, and SCN8A, encoding the Na+ channel pore-forming (α) subunits Nav1.1, 1.2, and 1.6, respectively, and SCN1B, encoding the accessory subunit β1 , are established causes of genetic epilepsies. SCN3A, encoding Nav1.3, is known to be highly expressed in brain, but has not previously been linked to early infantile epileptic encephalopathy...
February 21, 2018: Annals of Neurology
Xiaoming Zhang, Jin-Young Yoon, Michael Morley, Jared M McLendon, Kranti A Mapuskar, Rebecca Gutmann, Haider Mehdi, Heather L Bloom, Samuel C Dudley, Patrick T Ellinor, Alaa A Shalaby, Raul Weiss, W H Wilson Tang, Christine S Moravec, Madhurmeet Singh, Anne L Taylor, Clyde W Yancy, Arthur M Feldman, Dennis M McNamara, Kaikobad Irani, Douglas R Spitz, Patrick Breheny, Kenneth B Margulies, Barry London, Ryan L Boudreau
SCN5A encodes the voltage-gated Na+ channel NaV1.5 that is responsible for depolarization of the cardiac action potential and rapid intercellular conduction. Mutations disrupting the SCN5A coding sequence cause inherited arrhythmias and cardiomyopathy, and single-nucleotide polymorphisms (SNPs) linked to SCN5A splicing, localization, and function associate with heart failure-related sudden cardiac death. However, the clinical relevance of SNPs that modulate SCN5A expression levels remains understudied. We recently generated a transcriptome-wide map of microRNA (miR) binding sites in human heart, evaluated their overlap with common SNPs, and identified a synonymous SNP (rs1805126) adjacent to a miR-24 site within the SCN5A coding sequence...
February 19, 2018: Journal of Clinical Investigation
Kohei Takahara, Tadashi Yamamoto, Keiichiro Uchida, Hai-Lei Zhu, Atsushi Shibata, Tetsuichiro Inai, Mitsuru Noguchi, Mari Yotsu-Yamashita, Noriyoshi Teramoto
Molecular investigations were performed in order to determine the major characteristics of voltage-gated Na + channel β-subunits in mouse vas deferens. The use of real-time quantitative PCR showed that the expression of Scn1b was significantly higher than that of other β-subunit genes (Scn2b - Scn4b). Immunoreactivity of Scn1b proteins was also detected in the inner circular and outer longitudinal smooth muscle of mouse vas deferens. In whole-cell recordings, the actions of 4,9-anhydroTTX on voltage-gated Na + current peak amplitude in myocytes (i...
February 16, 2018: Naunyn-Schmiedeberg's Archives of Pharmacology
Yasuyoshi Tanaka, Takefumi Sone, Norimichi Higurashi, Tetsushi Sakuma, Sadafumi Suzuki, Mitsuru Ishikawa, Takashi Yamamoto, Jun Mitsui, Hitomi Tsuji, Hideyuki Okano, Shinichi Hirose
Dravet syndrome (DS) is an infantile epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene encoding the α1 subunit of the voltage-gated sodium channel Nav 1.1. As an in vitro model of this disease, we previously generated an induced pluripotent stem cell (iPSC) line from a patient with DS carrying a c.4933C>T (p.R1645*) substitution in SCN1A. Here, we describe developing a genome-edited control cell line from this DS iPSC line by substituting the point mutation with the wild-type residue...
February 2, 2018: Stem Cell Research
Fan Zhao, Wei Jin, Lin Ma, Jian-Ye Zhang, Jin-Long Wang, Jing-Hai Zhang, Yong-Bo Song
Voltage-gated sodium (Na v ) channels play a pivotal role for the changes in membrane potential and belong to large membrane proteins that compose four voltage sensor domains (VSD1-4). In this study we describe the binding mode and selectivity of one of the aryl sulfonamide sodium channel inhibitors, PF-04856264, for the VSD4s in Na v 1.4, Na v 1.5 and Na v 1.7, respectively, through molecular dynamics simulation and enhanced post-dynamics analyses. Our results show that there are three binding site regions (BSR1-3) in the combination of the ligand and receptors, of which BSR1 and BSR3 contribute to the selectivity and affinity of the ligand to the receptor...
February 15, 2018: Journal of Biomolecular Structure & Dynamics
Vladimir Rancic, Bijal Rawal, Bogdan Panaitescu, Araya Ruangkittisakul, Klaus Ballanyi
The brainstem locus coeruleus (LC) controling behaviors like arousal, sleep, breathing, pain or opioid withdrawal is an established model for spontaneous action potential synchronization. Such synchronous 'spiking' might produce an extracellular field potential (FP) which is a crucial tool for neural network analyses. We found using ≥10 μm tip diameter suction electrodes in newborn rat brainstem slices that the LC generates at ∼1 Hz a robust rhythmic FP (rFP). During distinct rFP phases, LC neurons discharge with a jitter of ±33 ms single spikes that summate to a ∼200 ms-lasting population burst...
February 12, 2018: Neuroscience Letters
Manindra Nath Tiwari, Sandesh Mohan, Yoav Biala, Yoel Yaari
In many types of CNS neurons, repetitive spiking produces a slow afterhyperpolarization (sAHP), providing sustained, intrinsically generated negative feedback to neuronal excitation. Changes in the sAHP have been implicated in learning behaviors, in cognitive decline in aging, and in epileptogenesis. Despite its importance in brain function, the mechanisms generating the sAHP are still controversial. Here we have addressed the roles of M-type K+ current (IM ), Ca2+ -gated K+ currents (ICa(K) 's) and Na+ /K+ -ATPases (NKAs) current to sAHP generation in adult rat CA1 pyramidal cells maintained at near-physiological temperature (35°C)...
February 12, 2018: Hippocampus
Yumiko Nishimura-Danjobara, Keisuke Oyama, Kumio Yokoigawa, Yasuo Oyama
To study the adverse effects of N-(3-oxododecanoyl)-l-homoserine-lactone (ODHL), a quorum sensing molecule, on mammalian host cells, its effect on membrane potential was examined in rat thymic lymphocytes using flow cytometric techniques with a voltage-sensitive fluorescent probe. As 3-300 μM ODHL elicited hyperpolarization, it is likely that it increases membrane K+ permeability because hyperpolarization is directly linked to changing K+ gradient across membranes, but not Na+ and Cl- gradients. ODHL did not increase intracellular Ca2+ concentration...
February 7, 2018: Chemico-biological Interactions
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