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Nav channels

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
Daniela Ponce-Balbuena, Guadalupe Guerrero-Serna, Carmen R Valdivia, Ricardo Caballero, F J Díez-Guerra, Eric N Jiménez-Vázquez, Rafael J Ramirez, Andre Monteiro da Rocha, Todd J Herron, Katherine F Campbell, B C Willis, Francisco J Alvarado, Manuel Zarzoso, Kuljeet Kaur, Marta Pérez-Hernández, Marcos Matamoros, Héctor H Valdivia, Eva Delpón, José Jalife
<u>Rationale:</u> In cardiomyocytes, NaV 1.5 and Kir2.1 channels interact dynamically as part of membrane bound macromolecular complexes. <u>Objective:</u> To test whether NaV 1.5 and Kir2.1 preassemble during early forward trafficking and travel together to common membrane microdomains. <u>Methods and Results:</u> In patch-clamp experiments, co-expression of trafficking deficient mutants Kir2.1Δ314-315 or Kir2.1R44A/R46A with wildtype (WT) NaV 1.5WT in heterologous cells reduced INa , compared to NaV 1...
March 7, 2018: Circulation Research
Marit Poffers, Nathalie Bühne, Christine Herzog, Anja Thorenz, Rongjun Chen, Faikah Güler, Axel Hage, Andreas Leffler, Frank Echtermeyer
BACKGROUND: Voltage-gated sodium channels generate action potentials in excitable cells, but they have also been attributed noncanonical roles in nonexcitable cells. We hypothesize that voltage-gated sodium channels play a functional role during extravasation of neutrophils. METHODS: Expression of voltage-gated sodium channels was analyzed by polymerase chain reaction. Distribution of Nav1.3 was determined by immunofluorescence and flow cytometry in mouse models of ischemic heart and kidney injury...
March 6, 2018: Anesthesiology
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
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
Kunsala T D S Yapa, Jennifer Deuis, Amelia A Peters, Paraic A Kenny, Sarah J Roberts-Thomson, Irina Vetter, Gregory R Monteith
AIMS: To assess levels of the calcium permeable transient receptor potential cation channel, subfamily melastatin, member 8 (TRPM8) in breast cancer molecular subtypes and to assess the consequences of TRPM8 pharmacological inhibition with AMTB (an inhibitor of TRPM8) on breast cancer cell lines. MATERIALS AND METHODS: Cell viability and migration of breast cancer cells was determined using MTS assays and wound healing assays, respectively. RNA-Seq analysis of breast tumours and qPCR in breast cancer cell lines were used to assess mRNA levels of ion channels...
February 26, 2018: Life Sciences
Mena Abdelsayed, Manpreet Ruprai, Peter C Ruben
E1784K is the most common mixed syndrome SCN5a mutation underpinning both Brugada syndrome type 1 (BrS1) and Long-QT syndrome type 3 (LQT3). The charge reversal mutant enhances the late sodium current (INa ) passed by the cardiac voltage-gated sodium channel (NaV 1.5), delaying cardiac repolarization. Exercise-induced triggers, like elevated temperature and cytosolic calcium, exacerbate E1784K late INa . In this study, we tested the effects of Ranolazine, the late INa blocker, on voltage-dependent and kinetic properties of E1784K at elevated temperature and cytosolic calcium...
February 26, 2018: Scientific Reports
Doreen Fialho, Robert C Griggs, Emma Matthews
The periodic paralyses are a group of skeletal muscle channelopathies characterizeed by intermittent attacks of muscle weakness often associated with altered serum potassium levels. The underlying genetic defects include mutations in genes encoding the skeletal muscle calcium channel Cav 1.1, sodium channel Nav 1.4, and potassium channels Kir 2.1, Kir 3.4, and possibly Kir 2.6. Our increasing knowledge of how mutant channels affect muscle excitability has resulted in better understanding of many clinical phenomena which have been known for decades and sheds light on some of the factors that trigger attacks...
2018: Handbook of Clinical Neurology
Ilya Pozdnyakov, Olga Matantseva, Sergei Skarlato
Four-domain voltage-gated cation channels (FVCCs) represent a large family of pseudo-tetrameric ion channels which includes voltage-gated calcium (Cav ) and sodium (Nav ) channels, as well as their homologues. These transmembrane proteins are involved in a wide range of physiological processes, such as membrane excitability, rhythmical activity, intracellular signalling, etc. Information about actual diversity and phylogenetic relationships of FVCCs across the eukaryotic tree of life is scarce. We for the first time performed a taxonomically broad phylogenetic analysis of 277 FVCC sequences from a variety of eukaryotes and showed that many groups of eukaryotic organisms have their own clades of FVCCs...
February 23, 2018: Scientific Reports
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
Man Liu, Guangbin Shi, Anyu Zhou, Cassady E Rupert, Kareen L K Coulombe, Samuel C Dudley
RATIONALE: Heart failure is characterized by electrical remodeling that contributes to arrhythmic risk. The unfolded protein response (UPR) is active in heart failure and can decrease protein levels by increasing mRNA decay, accelerating protein degradation, and inhibiting protein translation. OBJECTIVE: Therefore, we investigated whether the UPR downregulated cardiac ion channels that may contribute to arrhythmogenic electrical remodeling. METHODS: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study cardiac ion channels...
February 21, 2018: Journal of Molecular and Cellular Cardiology
César Mattei
Tetrodotoxin (TTX), the mode of action of which has been known since the 1960s, is widely used in pharmacology as a specific inhibitor of voltage-gated sodium channels (Nav channels). This toxin has contributed to the characterization of the allosteric model of the Nav channel, and to discriminating TTX-sensitive and TTX-resistant subtypes. In addition to its role as a pharmacological tool, TTX is now considered a therapeutic molecule, and its development should lead to its use in certain pathologies involving Nav channels, particularly in the field of pain...
February 22, 2018: Marine Drugs
Tetsuya Akaishi
Saltatory conduction is an essential phenomenon to facilitate the fast conduction in myelinated nerves. The conventional conductive models assumed electric circuits with local current along the axonal membrane to explain the nerve conduction in unmyelinated nerves. However, whether such models with local current can be also applied to the saltatory conduction in myelinated nerves is unknown. In this report, I propose a new model of saltatory conduction by focusing on the behavior of electric charges in the axoplasm, not limited to the membrane...
2018: Tohoku Journal of Experimental Medicine
Aleksandar Stojic, Jovana Bojcevski, Sarah K Williams, Ricarda Diem, Richard Fairless
Disturbances in the nodes of Ranvier are an early phenomenon in many CNS disorders, including the autoimmune demyelinating disease multiple sclerosis (MS). Using an animal model of optic neuritis, a common early symptom of MS, we have investigated nodal and paranodal compartments in the optic nerve during disease progression. Both nodes and paranodes, as identified by immunohistochemistry against sodium channels (Nav) and Caspr, respectively, were observed to increase in length during the late induction phase of the disease, prior to onset of the demyelination and immune cell infiltration characteristic of optic neuritis...
February 10, 2018: Journal of Neuropathology and Experimental Neurology
Fernanda C Cardoso, Mahadhi Hasan, Tianjiao Zhao, Richard J Lewis
PURPOSE OF REVIEW: Pain is a distressing protective sensory experience warning of actual or potential tissue damage. Natural toxins have evolved to exploit pain and related neuronal pathways to facilitate prey capture and for defence, often producing either numbness, paralysis or intense pain by selectively modulating ion channels and receptors in pain pathways. Understanding how toxins modulate pain pathways can enhance our understanding of the physiological and pathological basis of pain...
February 12, 2018: Current Opinion in Supportive and Palliative Care
M Kollarik, H Sun, R A Herbstsomer, F Ru, M Kocmalova, S N Meeker, B J Undem
The action potential (AP) initiation in the nerve terminals and AP conduction along the axons do not necessarily depend on the same subtypes of Na V 1s. We evaluated the role of tetrodotoxin(TTX)-sensitive and TTX-resistant Na V 1s in vagal afferent nociceptor nerves derived from jugular and nodose ganglia innervating the respiratory system. Single cell RT-PCR was performed on vagal afferent neurons retrogradely labelled from the guinea pig trachea. Virtually all the jugular neurons expressed the TTX-sensitive channel Na V 1...
February 12, 2018: Journal of Physiology
Gabriela de Azambuja Garcia, Mariana Rocha David, Ademir de Jesus Martins, Rafael Maciel de Freitas, Jutta Gerlinde Birggitt Linss, Simone Costa Araújo, José Bento Pereira Lima, Denise Valle
BACKGROUND: In the tropics, the utilization of insecticides is still an important strategy for controlling Aedes aegypti, the principle vector of dengue, chikungunya and Zika viruses. However, increasing insecticide resistance in Ae. aegypti populations might hinder insecticide efficacy on a long-term basis. It will be important to understand the dynamics and evolution of insecticide resistance by assessing its frequency and the mechanisms by which it occurs. METHODOLOGY/PRINCIPAL FINDINGS: The insecticide resistance status of four Brazilian Ae...
February 12, 2018: PLoS Neglected Tropical Diseases
Tzu-Tung Chang, Chia-Jung Yang, Yu-Chi Lee, Sheng-Nan Wu
Telmisartan (Tel) is recognized as a non-peptide blocker of angiotensin II type-1 receptor. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel increased the peak amplitude of voltage-gated Na⁺ current (INa) accompanied by the increased time constant of INa inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of angiotensin II receptors or activation of PPAR-γ...
January 29, 2018: Chinese Journal of Physiology
Katrin Schrenk-Siemens, Corinna Rösseler, Angelika Lampert
Chronic pain patients are often left with insufficient treatment as the pathophysiology especially of neuropathic pain remains enigmatic. Recently, genetic variations in the genes of the voltage-gated sodium channels (Navs) were linked to inherited neuropathic pain syndromes, opening a research pathway to foster our understanding of the pathophysiology of neuropathic pain. More than 10 years ago, the rare, inherited pain syndrome erythromelalgia was linked to mutations in the subtype Nav1.7, and since then a plethora of mutations and genetic variations in this and other Nav genes were identified...
January 28, 2018: Handbook of Experimental Pharmacology
Steven Molinarolo, Sora Lee, Lilia Leisle, John D Lueck, Daniele Granata, Vincenzo Carnevale, Christopher A Ahern
Voltage-gated, sodium ion-selective channels (NaV) generate electrical signals contributing to the upstroke of the action potential in animals. NaVs are also found in bacteria and are members of a larger family of tetrameric voltagegated channels that includes CaVs, KVs, and NaVs. Prokaryotic NaVs likely emerged from a homotetrameric Ca2+-selective voltage-gated progenerator, and later developed Na+ selectivity independently. The NaV signaling complex in eukaryotes contains auxiliary proteins, termed beta (β) subunits, which are potent modulators of the expression profiles and voltage-gated properties of the NaV pore, but it is unknown whether they can functionally interact with prokaryotic NaV channels...
January 25, 2018: Journal of Biological Chemistry
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