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Stephen G Waxman - One of the best experts on this subject based on the ideXlab platform.
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voltage gated Sodium Channels version 2019 4 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: William A Catterall, Alan L Goldin, Stephen G WaxmanAbstract:Sodium Channels are voltage-gated Sodium-selective ion Channels present in the membrane of most excitable cells. Sodium Channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits [176]. α-Subunits consist of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [268]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [268]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.The nomenclature for Sodium Channels was proposed by Goldin et al., (2000) [143] and approved by the NC-IUPHAR Subcommittee on Sodium Channels (Catterall et al., 2005, [51]).
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noncanonical roles of voltage gated Sodium Channels
Neuron, 2013Co-Authors: Joel A Black, Stephen G WaxmanAbstract:The Hodgkin-Huxley formulation, at its 60th anniversary, remains a bastion of neuroscience. Sodium Channels Nav1.1-Nav1.3 and Nav1.6-Nav1.9 support electrogenesis in neurons and are often considered "neuronal," whereas Nav1.4 and Nav1.5 drive electrogenesis in skeletal and cardiac muscle. These Channels are, however, expressed in cell types that are not considered electrically excitable. Here, we discuss Sodium channel expression in diverse nonexcitable cell types, including astrocytes, NG2 cells, microglia, macrophages, and cancer cells, and review evidence of noncanonical roles, including regulation of effector functions such as phagocytosis, motility, Na(+)/K(+)-ATPase activity, and metastatic activity. Armed with powerful techniques for monitoring channel activity and for real-time assessment of [Na(+)]i and [Ca(2+)]i, neuroscientists are poised to expand the understanding of noncanonical roles of Sodium Channels in healthy and diseased tissues.
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Sodium Channels in normal and pathological pain
Annual Review of Neuroscience, 2010Co-Authors: S Dibhajj, Theodore R. Cummins, Joel A Black, Stephen G WaxmanAbstract:Nociception is essential for survival whereas pathological pain is maladaptive and often unresponsive to pharmacotherapy. Voltage-gated Sodium Channels, Na(v)1.1-Na(v)1.9, are essential for generation and conduction of electrical impulses in excitable cells. Human and animal studies have identified several Channels as pivotal for signal transmission along the pain axis, including Na(v)1.3, Na(v)1.7, Na(v)1.8, and Na(v)1.9, with the latter three preferentially expressed in peripheral sensory neurons and Na(v)1.3 being upregulated along pain-signaling pathways after nervous system injuries. Na(v)1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders. Here we review the contribution of these Sodium channel isoforms to pain.
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voltage gated Sodium Channels therapeutic targets for pain
Pain Medicine, 2009Co-Authors: S Dibhajj, Joel A Black, Stephen G WaxmanAbstract:Objective. To provide an overview of the role of voltage-gated Sodium Channels in pathophysiology of acquired and inherited pain states, and of recent developments that validate these Channels as therapeutic targets for treating chronic pain. Background. Neuropathic and inflammatory pain conditions are major medical needs worldwide with only partial or low efficacy treatment options currently available. An important role of voltage-gated Sodium Channels in many different pain states has been established in animal models and, empirically, in humans, where Sodium channel blockers partially ameliorate pain. Animal studies have causally linked changes in Sodium channel expression and modulation that alter channel gating properties or current density in nociceptor neurons to different pain states. Biophysical and pharmacological studies have identified the Sodium channel isoforms Nav1.3, Nav1.7, Nav1.8, and Nav1.9 as particularly important in the pathophysiology of different pain syndromes. Recently, gain-of-function mutations in SCN9A , the gene which encodes Nav1.7, have been linked to two human-inherited pain syndromes, inherited erythromelalgia and paroxysmal extreme pain disorder, while loss-of-function mutations in SCN9A have been linked to complete insensitivity to pain. Studies on firing properties of sensory neurons of dorsal root ganglia demonstrate that the effects of gain-of-function mutations in Nav1.7 on the excitability of these neurons depend on the presence of Nav1.8, which suggests a similar physiological interaction of these two Channels in humans carrying the Nav1.7 pain mutation. Conclusions. These studies suggest that isoform-specific blockers of these Channels or targeting of their modulators may provide novel approaches to treatment of pain.
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mechanisms of disease Sodium Channels and neuroprotection in multiple sclerosis current status
Nature Reviews Neurology, 2008Co-Authors: Stephen G WaxmanAbstract:Axon degeneration is a major contributor to disability in multiple sclerosis, and Sodium Channels have been shown to have a crucial role in this process. In this article, Waxman reviews the development of the concept of Sodium channel blockers as neuroprotectants in multiple sclerosis, and discusses recent attempts to translate this approach from the laboratory to the clinic. Sodium Channels can provide a route for a persistent influx of Sodium ions into neurons. Over the past decade, it has emerged that sustained Sodium influx can, in turn, trigger calcium ion influx, which produces axonal injury in neuroinflammatory disorders such as multiple sclerosis (MS). The development of Sodium channel blockers as potential neuroprotectants in MS has proceeded rapidly, and two clinical trials are currently ongoing. The route from the laboratory to the clinic includes some complex turns, however, and a third trial was recently put on hold because of new data that suggested that Sodium channel blockers might have multiple, complex actions. This article reviews the development of the concept of Sodium channel blockers as neuroprotectants in MS, the path from laboratory to clinic, and the current status of research in this area.
Toshio Narahashi - One of the best experts on this subject based on the ideXlab platform.
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voltage dependent block of Sodium Channels in mammalian neurons by the oxadiazine insecticide indoxacarb and its metabolite dcjw
Neurotoxicology, 2003Co-Authors: Xilong Zhao, Jay Z Yeh, Tomoko Ikeda, Toshio NarahashiAbstract:Abstract Indoxacarb is a newly developed insecticide with high insecticidal activity and low toxicity to non-target organisms. Its metabolite, DCJW, is known to block compound action potentials in insect nerves and to inhibit Sodium currents in cultured insect neurons. However, little is known about the effects of these compounds on the Sodium Channels of mammalian neurons. We compared the effects of indoxacarb and DCJW on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Sodium Channels in rat dorsal root ganglion neurons by using the whole-cell patch clamp technique. Indoxacarb and DCJW at 1–10 μM slowly and irreversibly blocked both TTX-S and TTX-R Sodium Channels in a voltage-dependent manner. The Sodium channel activation kinetics were not significantly modified by 1 μM indoxacarb or 1 μM DCJW. The steady-state fast and slow inactivation curves were shifted in the hyperpolarization direction by 1 μM indoxacarb or 1 μM DCJW indicating a higher affinity of the inactivated Sodium Channels for these insecticides. These shifts resulted in an enhanced block at more depolarized potentials, thus explaining voltage-dependent block, and an apparent difference in the sensitivity of TTX-R and TTX-S Channels to indoxacarb and DCJW near the resting potential. Indoxacarb and its metabolite DCJW cause toxicity through their action on the Sodium Channels.
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differential action of riluzole on tetrodotoxin sensitive and tetrodotoxin resistant Sodium Channels
Journal of Pharmacology and Experimental Therapeutics, 1997Co-Authors: Jinho Song, Chao Sheng Huang, Keiichi Nagata, Jay Z Yeh, Toshio NarahashiAbstract:The effects of riluzole, a neuroprotective drug, on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Sodium Channels in rat dorsal root ganglion neurons were studied using the whole-cell patch clamp technique. At the resting potential, riluzole preferentially blocked TTX-S Sodium Channels, whereas at more negative potentials, it blocked both types of Sodium Channels almost equally. The apparent dissociation constants for riluzole to block TTX-S and TTX-R Sodium Channels in their resting state were 90 and 143 μM, respectively. Riluzole shifted the voltage dependence of activation of TTX-R Sodium Channels in the depolarizing direction more than that of TTX-S Sodium Channels. The voltage dependence of the fast inactivation of both types of Sodium Channels was shifted in the hyperpolarizing direction in a dose-dependent manner, and the apparent dissociation constants for riluzole to block the inactivated Channels were estimated to be 2 and 3 μM for the TTX-S and TTX-R Sodium Channels, respectively, indicating a much higher affinity for the inactivated Channels than for the resting Channels. Riluzole was equally effective in blocking both types of Sodium Channels in their slow inactivated state. Since more TTX-S Channels are inactivated than TTX-R Channels at the resting potential, riluzole blocks TTX-S Sodium Channels more potently than TTX-R Sodium Channels. It was concluded that one of the mechanisms by which riluzole exerts its neuroprotective action is to preferentially block the inactivated Sodium channel of damaged or depolarized neurons under ischemic conditions, thereby suppressing excess stimulation of the glutamatergic receptors and massive influx of Ca++.
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modulation of Sodium Channels of rat cerebellar purkinje neurons by the pyrethroid tetramethrin
Journal of Pharmacology and Experimental Therapeutics, 1996Co-Authors: J. H. Song, Toshio NarahashiAbstract:The pyrethroid insecticides are known to slow the kinetics of the activation and inactivation gates of Sodium Channels. This results in prolonged openings of individual Sodium Channels and prolonged flow of whole-cell Sodium current, which in turn cause hyperexcitation in animals. The aim of the present study was to solve three important remaining questions. First, the percentages of the Sodium Channels modified by the pyrethroid tetramethrin were measured and compared with the threshold concentration to initiate repetitive discharges in rat cerebellar Purkinje neurons. Tetramethrin at 0.1 microM modified only 0.6% of the Sodium Channels and generated repetitive afterdischarges. Thus, the pyrethroid toxicity is greatly amplified from the Sodium channel to the whole animal. The pyrethroid sensitivity of Purkinje neuron Sodium Channels was lower than that of invertebrate Sodium Channels by a factor of > or = 10. Chloramine-T at 200 microM removed the Sodium channel inactivation and increased the percentage of Sodium channel modification by tetramethrin through open channel modification. Second, temperature had a profound effect on the ability of tetramethrin to cause repetitive afterdischarges; at 0.1 to 0.3 microM tetramethrin, repetitive discharges were induced at l5 degrees C and 20 degrees C, but this effect subsided at 25 degrees C to 35 degrees C. This negative temperature dependence could be explained by an increase in charge movement during slow tail current as temperature was lowered. The Q10 value for the charge movement during tail current was 0.22 between 20 degrees C and 30 degrees C. Third, the selective toxicity of pyrethroids between mammals and insects could be explained quantitatively on the basis of Sodium channel factors that include temperature dependence, intrinsic sensitivity and recovery rate and detoxication factors.
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selective block of tetramethrin modified Sodium Channels by alpha tocopherol vitamin e
Journal of Pharmacology and Experimental Therapeutics, 1995Co-Authors: Jinho Song, Toshio NarahashiAbstract:Pyrethroids exert their hyperexcitatory effects by prolonging the open time of individual neuronal Sodium Channels. Occupational exposure to pyrethroids frequently leads to abnormal skin sensation or paresthesia. Vitamin E is known to reduce the cutaneous paresthesia. However, the mechanism of action has been totally unclear. Because the Sodium channel is the major target site of pyrethroids, it is possible that vitamin E interferes with pyrethroid modification of the Sodium channel. Patch clamp experiments were performed using rat dorsal root ganglion neurons and cerebellar Purkinje cells. (+/-)-alpha-Tocopherol (vitamin E) selectively blocked the tetramethrin(type I pyrethroid)-modified Sodium Channels in a dose-dependent, but voltage-independent manner without affecting normal Sodium Channels. The concentration-response curves for tetramethrin modification of the Sodium Channels were shifted in the direction of higher concentrations by (+/-)-alpha-tocopherol in a competitive manner. Elevated depolarizing after-potential or repetitive after-discharges caused by tetramethrin were effectively blocked by (+/-)-alpha-tocopherol. (+/-)-alpha-Tocopherol did not reverse the tetramethrin-induced shift in the current-voltage curve for peak Sodium current, but partially reversed the shift in the steady-state Sodium channel inactivation curve. Vitamin A and its metabolic derivative, retinoic acid, slightly reduced both normal and tetramethrin-modified Sodium currents. The selective block of tetramethrin-modified Sodium Channels by (+/-)-alpha-tocopherol is one of the important mechanisms underlying (+/-)-alpha-tocopherol alleviation of paresthesia.
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differential mechanism of action of the pyrethroid tetramethrin on tetrodotoxin sensitive and tetrodotoxin resistant Sodium Channels
Journal of Pharmacology and Experimental Therapeutics, 1994Co-Authors: Hideharu Tatebayashi, Toshio NarahashiAbstract:Rat dorsal root ganglion neurons are endowed with tetrodotoxin-sensitive(TTX-S) and tetrodotoxin-resistant (TTX-R) Sodium Channels. The pyrethroid insecticides, which are known to keep Sodium Channels open for a prolonged period of time, cause differential effects on the two types of Sodium Channels. The whole-cell patch clamp experiments were performed with rat dorsal root ganglion neurons in primary culture. In TTX-S Sodium Channels, the slow Sodium current during step depolarization was increased somewhat by tetramethrin, and a tail Sodium current with a slowly rising and falling phase appeared upon repolarization. The tail current developed even after the Sodium current during depolarization had subsided. In TTX-R Sodium Channels, the slow Sodium current during step depolarization was increased markedly by tetramethrin, and upon repolarization a large instantaneous tail current was generated and decayed slowly. The steady-state Sodium channel inactivation curve was shifted by tetramethrin in the hyperpolarizing direction in both TTX-S and TTX-R Channels. The Sodium conductance-voltage curve also was shifted by tetramethrin in the hyperpolarizing direction in both TTX-S and TTX-R Channels, and the latter was affected more strongly than the former. At a concentration of 10 microM, the highest concentration tested, tetramethrin modified only 12% of the TTX-S Sodium Channels, whereas the modification was as high as 81% in the TTX-R. Even at 10 nM, 1.3% of TTX-R Sodium Channels were modified; this accounts for the high potency of tetramethrin as an insecticide.(ABSTRACT TRUNCATED AT 250 WORDS)
William A Catterall - One of the best experts on this subject based on the ideXlab platform.
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voltage gated Sodium Channels version 2019 4 in the iuphar bps guide to pharmacology database
IUPHAR BPS Guide to Pharmacology CITE, 2019Co-Authors: William A Catterall, Alan L Goldin, Stephen G WaxmanAbstract:Sodium Channels are voltage-gated Sodium-selective ion Channels present in the membrane of most excitable cells. Sodium Channels comprise of one pore-forming α subunit, which may be associated with either one or two β subunits [176]. α-Subunits consist of four homologous domains (I–IV), each containing six transmembrane segments (S1–S6) and a pore-forming loop. The positively charged fourth transmembrane segment (S4) acts as a voltage sensor and is involved in channel gating. The crystal structure of the bacterial NavAb channel has revealed a number of novel structural features compared to earlier potassium channel structures including a short selectivity filter with ion selectivity determined by interactions with glutamate side chains [268]. Interestingly, the pore region is penetrated by fatty acyl chains that extend into the central cavity which may allow the entry of small, hydrophobic pore-blocking drugs [268]. Auxiliary β1, β2, β3 and β4 subunits consist of a large extracellular N-terminal domain, a single transmembrane segment and a shorter cytoplasmic domain.The nomenclature for Sodium Channels was proposed by Goldin et al., (2000) [143] and approved by the NC-IUPHAR Subcommittee on Sodium Channels (Catterall et al., 2005, [51]).
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Forty Years of Sodium Channels: Structure, Function, Pharmacology, and Epilepsy
Neurochemical Research, 2017Co-Authors: William A CatterallAbstract:Voltage-gated Sodium Channels initiate action potentials in brain neurons. In the 1970s, much was known about the function of Sodium Channels from measurements of ionic currents using the voltage clamp method, but there was no information about the Sodium channel molecules themselves. As a postdoctoral fellow and staff scientist at the National Institutes of Health, I developed neurotoxins as molecular probes of Sodium Channels in cultured neuroblastoma cells. During those years, Bruce Ransom and I crossed paths as members of the laboratories of Marshall Nirenberg and Philip Nelson and shared insights about Sodium Channels in neuroblastoma cells from my work and electrical excitability and synaptic transmission in cultured spinal cord neurons from Bruce’s pioneering electrophysiological studies. When I established my laboratory at the University of Washington in 1977, my colleagues and I used those neurotoxins to identify the protein subunits of Sodium Channels, purify them, and reconstitute their ion conductance activity in pure form. Subsequent studies identified the molecular basis for the main functions of Sodium Channels—voltage-dependent activation, rapid and selective ion conductance, and fast inactivation. Bruce Ransom and I re-connected in the 1990s, as ski buddies at the Winter Conference on Brain Research and as faculty colleagues at the University of Washington when Bruce became our founding Chair of Neurology and provided visionary leadership of that department. In the past decade my work on Sodium Channels has evolved into structural biology. Molecular modeling and X-ray crystallographic studies have given new views of Sodium channel function at atomic resolution. Sodium Channels are also the molecular targets for genetic diseases, including Dravet Syndrome, an intractable pediatric epilepsy disorder with major co-morbidities of cognitive deficit, autistic-like behaviors, and premature death that is caused by loss-of-function mutations in the brain Sodium channel Na_V1.1. Our work on a mouse genetic model of this disease has shown that its multi-faceted pathophysiology and co-morbidities derive from selective loss of electrical excitability and action potential firing in GABAergic inhibitory neurons, which disinhibits neural circuits throughout the brain and leads directly to the epilepsy, premature death and complex co-morbidities of this disease. It has been rewarding for me to use our developing knowledge of Sodium Channels to help understand the pathophysiology and to suggest potential therapeutic approaches for this devastating childhood disease.
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Sodium Channels inherited epilepsy and antiepileptic drugs
Annual Review of Pharmacology and Toxicology, 2014Co-Authors: William A CatterallAbstract:Voltage-gated Sodium Channels initiate action potentials in brain neurons, mutations in Sodium Channels cause inherited forms of epilepsy, and Sodium channel blockers-along with other classes of drugs-are used in therapy of epilepsy. A mammalian voltage-gated Sodium channel is a complex containing a large, pore-forming α subunit and one or two smaller β subunits. Extensive structure-function studies have revealed many aspects of the molecular basis for Sodium channel structure, and X-ray crystallography of ancestral bacterial Sodium Channels has given insight into their three-dimensional structure. Mutations in Sodium channel α and β subunits are responsible for genetic epilepsy syndromes with a wide range of severity, including generalized epilepsy with febrile seizures plus (GEFS+), Dravet syndrome, and benign familial neonatal-infantile seizures. These seizure syndromes are treated with antiepileptic drugs that offer differing degrees of success. The recent advances in understanding of disease mechanisms and Sodium channel structure promise to yield improved therapeutic approaches.
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structure and function of voltage gated Sodium Channels at atomic resolution
Experimental Physiology, 2014Co-Authors: William A CatterallAbstract:New Findings • What is the topic of this review?The central goal of the research reviewed here is to understand the functional properties of voltage-gated Sodium Channels at the level of high-resolution structure of the channel protein. • What advances does it highlight?The key functional properties of voltage-gated Sodium Channels, including voltage-dependent activation. Sodium conductance and selectivity, block by local anesthetics and related drugs, and both fast and slow inactivation, are now understood at the level of protein structure with high resolution. These emerging high-resolution structural models may lead to development of safer and more efficacious drugs for treatment of epilepsy, chronic pain, and cardiac arrhythmia through structure-based drug design. Voltage-gated Sodium Channels initiate action potentials in nerve, muscle and other excitable cells. Early physiological studies described Sodium selectivity, voltage-dependent activation and fast inactivation, and developed conceptual models for Sodium channel function. This review article follows the topics of my 2013 Sharpey-Schafer Prize Lecture and gives an overview of research using a combination of biochemical, molecular biological, physiological and structural biological approaches that have elucidated the structure and function of Sodium Channels at the atomic level. Structural models for voltage-dependent activation, Sodium selectivity and conductance, drug block and both fast and slow inactivation are discussed. A perspective for the future envisions new advances in understanding the structural basis for Sodium channel function and the opportunity for structure-based discovery of novel therapeutics.
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voltage gated Sodium Channels at 60 structure function and pathophysiology
The Journal of Physiology, 2012Co-Authors: William A CatterallAbstract:Voltage-gated Sodium Channels initiate action potentials in nerve, muscle and other excitable cells. The Sodium current that initiates the nerve action potential was discovered by Hodgkin and Huxley using the voltage clamp technique in their landmark series of papers in The Journal of Physiology in 1952. They described Sodium selectivity, voltage-dependent activation and fast inactivation, and they developed a quantitative model for action potential generation that has endured for many decades. This article gives an overview of the legacy that has evolved from their work, including development of conceptual models of Sodium channel function, discovery of the Sodium channel protein, analysis of its structure and function, determination of its structure at high resolution, definition of the mechanism and structural basis for drug block, and exploration of the role of the Sodium channel as a target for disease mutations. Structural models for Sodium selectivity and conductance, voltage-dependent activation, fast inactivation and drug block are discussed. A perspective for the future envisions new advances in understanding the structural basis for Sodium channel function, the role of Sodium Channels in disease and the opportunity for discovery of novel therapeutics.
B. W. Urban - One of the best experts on this subject based on the ideXlab platform.
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Pharmacological modification of Sodium Channels from the human heart atrium in planar lipid bilayers: electrophysiological characterization of responses to batrachotoxin and pentobarbital.
European journal of anaesthesiology, 2003Co-Authors: H. C. Wartenberg, J. P. Wartenberg, B. W. UrbanAbstract:Summary Background and objective: To investigate the effects of barbiturates on batrachotoxin-modified Sodium Channels from different regions of the human heart. Single Sodium Channels from human atria were studied and compared with existing data from the human ventricle and from the central nervous system. Methods: Sodium Channels from preparations of human atrial muscle were incorporated into planar lipid bilayers in the presence of batrachotoxin, a Sodium channel activator. The steady-state behaviour of single Sodium Channels was recorded in symmetrical 500 mmol NaCl before and after the addition of pentobarbital 0.34 ‐1.34 mmol. Results: The batrachotoxin-treated human atrial Sodium channel had an average single-channel conductance of 23.8 6 1.6 pS in symmetrical 500 mmol NaCl and a channel fractional open time of 0.83 6 0.06. The activation mid-point potential was 298.0 6 2.3 mV. Extracellular tetrodotoxin (a specific Sodium channel blocking agent) blocked these Channels with a k 1/2 5 0.53 µ mol at 0 mV. Pentobarbital reduced the time average conductance of single atrial Sodium Channels in a concentration-dependent manner (ID 50 5 0.71 mmol). In the same way, the steady-state activation was shifted to more hyperpolarized potentials ( 210.6 mV at 0.67 mmol pentobarbital). Conclusions: The properties of batrachotoxin-modified Sodium Channels from human atrial tissue did not differ greatly from those described for ventricular Sodium Channels in the literature. Our data yielded no explanation for the observed functional diversity. However, cardiac Sodium Channels differ from those found in the central nervous system.
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human cardiac Sodium Channels are affected by pentobarbital
European Journal of Anaesthesiology, 2001Co-Authors: H. C. Wartenberg, J. P. Wartenberg, B. W. UrbanAbstract:Summary Background and objective To investigate the response to general anaesthetics of different Sodium channel subtypes, we examined the effects of pentobarbital, a close thiopental analogue, on single Sodium Channels from human ventricular muscle and compared them with existing data from human brain Channels. Methods Sodium Channels from preparations of human ventricular muscle were incorporated into planar lipid bilayers in the presence of batrachotoxin, a Sodium channel activator. Single channel currents were recorded in symmetrical 100 mmol L−1 and 500 mmol L−1 NaCl before and after the addition of the anaesthetic pentobarbital (0.34–1.34 mmol L−1). Results The blocking effect of pentobarbital on the fractional open time had an IC50 of 690 µmol L−1 in 500 mmol L−1 NaCl, whereas it had a significantly lower IC50 of 400 µmol L−1 in 100 mmol L−1 NaCl. Pentobarbital caused a significant shift of steady-state activation to hyperpolarized potentials (fmax = −42 mV, IC50 = 2 mmol L−1). This effect was independent of NaCl concentration. Conclusion Despite pharmacological and electrophysiological differences between human cardiac and human brain Sodium Channels their responses to pentobarbital are similar. The finding of channel block being dependent on the electrolyte concentration is novel for Sodium Channels.
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the voltage dependent action of pentobarbital on batrachotoxin modified human brain Sodium Channels
Biochimica et Biophysica Acta, 1994Co-Authors: Benno Rehberg, Daniel S Duch, B. W. UrbanAbstract:The voltage-dependent action of the intravenous anesthetic pentobarbital on human brain Sodium Channels activated by batrachotoxin was examined using planar lipid bilayer methods. Fractional open time-data were fitted by Boltzmann functions to yield simple parameters characterizing the voltage-dependence of the fractional open time. Pentobarbital caused a dose-dependent reduction of the maximum fractional open time of the Sodium channel and a shift of the potential of half-maximal open time towards hyperpolarized potentials, whereas the slope parameter of the Boltzmann-fits was unaffected. A statistically significant increase of the variability of these parameters was found only in the case of the maximum fractional open time, indicating a random fluctuation of pentobarbital-induced suppression of the Sodium Channels over time. The voltage-dependent action of pentobarbital probably results from either a pentobarbital-modification of channel activation gating and/or a modification of the pentobarbital action by the gating process itself.
Joel A Black - One of the best experts on this subject based on the ideXlab platform.
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noncanonical roles of voltage gated Sodium Channels
Neuron, 2013Co-Authors: Joel A Black, Stephen G WaxmanAbstract:The Hodgkin-Huxley formulation, at its 60th anniversary, remains a bastion of neuroscience. Sodium Channels Nav1.1-Nav1.3 and Nav1.6-Nav1.9 support electrogenesis in neurons and are often considered "neuronal," whereas Nav1.4 and Nav1.5 drive electrogenesis in skeletal and cardiac muscle. These Channels are, however, expressed in cell types that are not considered electrically excitable. Here, we discuss Sodium channel expression in diverse nonexcitable cell types, including astrocytes, NG2 cells, microglia, macrophages, and cancer cells, and review evidence of noncanonical roles, including regulation of effector functions such as phagocytosis, motility, Na(+)/K(+)-ATPase activity, and metastatic activity. Armed with powerful techniques for monitoring channel activity and for real-time assessment of [Na(+)]i and [Ca(2+)]i, neuroscientists are poised to expand the understanding of noncanonical roles of Sodium Channels in healthy and diseased tissues.
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Sodium Channels in normal and pathological pain
Annual Review of Neuroscience, 2010Co-Authors: S Dibhajj, Theodore R. Cummins, Joel A Black, Stephen G WaxmanAbstract:Nociception is essential for survival whereas pathological pain is maladaptive and often unresponsive to pharmacotherapy. Voltage-gated Sodium Channels, Na(v)1.1-Na(v)1.9, are essential for generation and conduction of electrical impulses in excitable cells. Human and animal studies have identified several Channels as pivotal for signal transmission along the pain axis, including Na(v)1.3, Na(v)1.7, Na(v)1.8, and Na(v)1.9, with the latter three preferentially expressed in peripheral sensory neurons and Na(v)1.3 being upregulated along pain-signaling pathways after nervous system injuries. Na(v)1.7 is of special interest because it has been linked to a spectrum of inherited human pain disorders. Here we review the contribution of these Sodium channel isoforms to pain.
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voltage gated Sodium Channels therapeutic targets for pain
Pain Medicine, 2009Co-Authors: S Dibhajj, Joel A Black, Stephen G WaxmanAbstract:Objective. To provide an overview of the role of voltage-gated Sodium Channels in pathophysiology of acquired and inherited pain states, and of recent developments that validate these Channels as therapeutic targets for treating chronic pain. Background. Neuropathic and inflammatory pain conditions are major medical needs worldwide with only partial or low efficacy treatment options currently available. An important role of voltage-gated Sodium Channels in many different pain states has been established in animal models and, empirically, in humans, where Sodium channel blockers partially ameliorate pain. Animal studies have causally linked changes in Sodium channel expression and modulation that alter channel gating properties or current density in nociceptor neurons to different pain states. Biophysical and pharmacological studies have identified the Sodium channel isoforms Nav1.3, Nav1.7, Nav1.8, and Nav1.9 as particularly important in the pathophysiology of different pain syndromes. Recently, gain-of-function mutations in SCN9A , the gene which encodes Nav1.7, have been linked to two human-inherited pain syndromes, inherited erythromelalgia and paroxysmal extreme pain disorder, while loss-of-function mutations in SCN9A have been linked to complete insensitivity to pain. Studies on firing properties of sensory neurons of dorsal root ganglia demonstrate that the effects of gain-of-function mutations in Nav1.7 on the excitability of these neurons depend on the presence of Nav1.8, which suggests a similar physiological interaction of these two Channels in humans carrying the Nav1.7 pain mutation. Conclusions. These studies suggest that isoform-specific blockers of these Channels or targeting of their modulators may provide novel approaches to treatment of pain.
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Sodium Channels contribute to microglia macrophage activation and function in eae and ms
Glia, 2005Co-Authors: Matthew J. Craner, Jia Newcombe, Joel A Black, Tina G Damarjian, Shujun Liu, Bryan C Hains, Louise M Cuzner, Stephen G WaxmanAbstract:Loss of axons is a major contributor to nonremitting deficits in the inflammatory demyelinating disease multiple sclerosis (MS). Based on biophysical studies showing that activity of axonal Sodium Channels can trigger axonal degeneration, recent studies have tested Sodium channel-blocking drugs in experimental autoimmune encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on axons. However, it is possible that, in addition to a direct effect on axons, Sodium channel blockers may also interfere with inflammatory mechanisms. We therefore examined the novel hypothesis that Sodium Channels contribute to activation of microglia and macrophages in EAE and acute MS lesions. In this study, we demonstrate a robust increase of Sodium channel Nav1.6 expression in activated microglia and macrophages in EAE and MS. We further demonstrate that treatment with the Sodium channel blocker phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75%. Supporting a role for Sodium Channels in microglial activation, we show that tetrodotoxin, a specific Sodium channel blocker, reduces the phagocytic function of activated rat microglia by 40%. To further confirm a role of Nav1.6 in microglial activation, we examined the phagocytic capacity of microglia from med mice, which lack Nav1.6 Channels, and show a 65% reduction in phagocytic capacity compared with microglia from wildtype mice. Our findings indicate that Sodium Channels are important for activation and phagocytosis of microglia and macrophages in EAE and MS and suggest that, in addition to a direct neuroprotective effect on axons, Sodium channel blockade may ameliorate neuroinflammatory disorders via anti-inflammatory mechanisms.
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changes in the expression of tetrodotoxin sensitive Sodium Channels within dorsal root ganglia neurons in inflammatory pain
Pain, 2004Co-Authors: Joel A Black, Theodore R. Cummins, Shujun Liu, Masaki Tanaka, Stephen G WaxmanAbstract:Nociceptive neurons within dorsal root ganglia (DRG) express multiple voltage-gated Sodium Channels, of which the tetrodotoxin-resistant (TTX-R) channel Na(v)1.8 has been suggested to play a major role in inflammatory pain. Previous work has shown that acute administration of inflammatory mediators, including prostaglandin E2 (PGE2), serotonin, and adenosine, modulates TTX-R current in DRG neurons, producing increased current amplitude and a hyperpolarizing shift of its activation curve. In addition, 4 days following injection of carrageenan into the hind paw, an established model of inflammatory pain, Na(v)1.8 mRNA and slowly-inactivating TTX-R current are increased in DRG neurons projecting to the affected paw. In the present study, the expression of Sodium Channels Na(v)1.1-Na(v)1.9 in small (< or = 25 micromdiameter) DRG neurons was examined with in situ hybridization, immunocytochemistry, Western blot and whole-cell patch-clamp methods following carrageenan injection into the peripheral projection fields of these cells. The results demonstrate that, following carrageenan injection, there is increased expression of TTX-S Channels Na(v)1.3 and Na(v)1.7 and a parallel increase in TTX-S currents. The previously reported upregulation of Na(v)1.8 and slowly-inactivating TTX-R current is not accompanied by upregulation of mRNA or protein for Na(v)1.9, an additional TTX-R channel that is expressed in some DRG neurons. These observations demonstrate that chronic inflammation results in an upregulation in the expression of both TTX-S and TTX-R Sodium Channels, and suggest that TTX-S Sodium Channels may also contribute, at least in part, to pain associated with inflammation.
