The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Bruce P Bean - One of the best experts on this subject based on the ideXlab platform.
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persistent Sodium Current drives conditional pacemaking in ca1 pyramidal neurons under muscarinic stimulation
The Journal of Neuroscience, 2013Co-Authors: Jason Yamadahanff, Bruce P BeanAbstract:Hippocampal CA1 pyramidal neurons are normally quiescent but can fire spontaneously when stimulated by muscarinic agonists. In brain slice recordings from mouse CA1 pyramidal neurons, we examined the ionic basis of this activity using interleaved Current-clamp and voltage-clamp experiments. Both in control and after muscarinic stimulation, the steady-state Current–voltage curve was dominated by inward TTX-sensitive persistent Sodium Current (INaP) that activated near −75 mV and increased steeply with depolarization. In control, total membrane Current was net outward (hyperpolarizing) near −70 mV so that cells had a stable resting potential. Muscarinic stimulation activated a small nonselective cation Current so that total membrane Current near −70 mV shifted to become barely net inward (depolarizing). The small depolarization triggers regenerative activation of INaP, which then depolarizes the cell from −70 mV to spike threshold. We quantified the relative contributions of INaP, hyperpolarization-activated cation Current (Ih), and calcium Current to pacemaking by using the cell's own firing as a voltage command along with specific blockers. TTX-sensitive Sodium Current was substantial throughout the entire interspike interval, increasing as the membrane potential approached threshold, while both Ih and calcium Current were minimal. Thus, spontaneous activity is driven primarily by activation of INaP in a positive feedback loop starting near −70 mV and providing increasing inward Current to threshold. These results show that the pacemaking “engine” from INaP is an inherent property of CA1 pyramidal neurons that can be engaged or disengaged by small shifts in net membrane Current near −70 mV, as by muscarinic stimulation.
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transient Sodium Current at subthreshold voltages activation by epsp waveforms
Neuron, 2012Co-Authors: Brett C Carter, Andrew J Giessel, Bernardo L Sabatini, Bruce P BeanAbstract:Summary Tetrodotoxin (TTX)-sensitive Sodium channels carry large transient Currents during action potentials and also "persistent" Sodium Current, a noninactivating TTX-sensitive Current present at subthreshold voltages. We examined gating of subthreshold Sodium Current in dissociated cerebellar Purkinje neurons and hippocampal CA1 neurons, studied at 37°C with near-physiological ionic conditions. Unexpectedly, in both cell types small voltage steps at subthreshold voltages activated a substantial component of transient Sodium Current as well as persistent Current. Subthreshold EPSP-like waveforms also activated a large component of transient Sodium Current, but IPSP-like waveforms engaged primarily persistent Sodium Current with only a small additional transient component. Activation of transient as well as persistent Sodium Current at subthreshold voltages produces amplification of EPSPs that is sensitive to the rate of depolarization and can help account for the dependence of spike threshold on depolarization rate, as previously observed in vivo.
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The Molecular Machinery of Resurgent Sodium Current Revealed
Neuron, 2005Co-Authors: Bruce P BeanAbstract:Abstract Some TTX-sensitive Sodium channels open transiently during recovery from inactivation, generating a "resurgent" Sodium Current that flows immediately following action potentials. In this issue of Neuron , Grieco and colleagues present evidence that resurgent Sodium Current results from a novel form of inactivation in which the cytoplasmic tail of the β4 subunit acts as a classic open-channel blocker.
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subthreshold Sodium Current from rapidly inactivating Sodium channels drives spontaneous firing of tuberomammillary neurons
Neuron, 2002Co-Authors: Abraha Taddese, Bruce P BeanAbstract:Abstract A role for "persistent," subthreshold, TTX-sensitive Sodium Current in driving the pacemaking of many central neurons has been proposed, but this has been impossible to test pharmacologically. Using isolated tuberomammillary neurons, we assessed the role of subthreshold Sodium Current in pacemaking by performing voltage-clamp experiments using a cell's own pacemaking cycle as voltage command. TTX-sensitive Sodium Current flows throughout the pacemaking cycle, even at voltages as negative as −70 mV, and this Current is sufficient to drive spontaneous firing. When Sodium channels underlying transient Current were driven into slow inactivation by rapid stimulation, persistent Current decreased in parallel, suggesting that persistent Sodium Current originates from subthreshold gating of the same Sodium channels that underlie the phasic Sodium Current. This behavior of Sodium channels may endow all neurons with an intrinsic propensity for rhythmic, spontaneous firing.
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resurgent Sodium Current and action potential formation in dissociated cerebellar purkinje neurons
The Journal of Neuroscience, 1997Co-Authors: Indira M Raman, Bruce P BeanAbstract:Voltage-dependent Sodium channels were studied in dissociated cerebellar Purkinje neurons from rats. In whole-cell recordings, a tetrodotoxin (TTX)-sensitive inward Current was elicited when the membrane was repolarized to voltages between −60 and −20 mV after depolarizations to +30 mV long enough to produce maximal inactivation. At −40 mV, this “resurgent” Current peaked in 8 msec and decayed with a time constant of 30 msec. With 50 mm Sodium as a charge carrier, the resurgent Current was on average ∼120 pA. CA3 pyramidal neurons had no such Current. The Current may reflect recovery of inactivated channels through open states, because in Purkinje neurons (but not CA3 neurons) there was partial recovery from inactivation at −40 mV, coinciding with the rise of resurgent Current. In single-channel recordings, individual channels gave openings corresponding to resurgent and conventional transient Current. Action potentials were recorded from dissociated neurons under Current clamp to investigate the role of the resurgent Current in action potential formation. Purkinje neurons fired spontaneously at ∼30 Hz. Hyperpolarization to −85 mV prevented spontaneous firing, and brief depolarization then induced all-or-none firing of conglomerate action potentials comprising three to four spikes. When conglomerate action potentials were used as command voltages in voltage-clamp experiments, TTX-sensitive Sodium Current was elicited between spikes. The falling phase of an action potential is similar to voltage patterns that activate resurgent Sodium Current, and thus, resurgent Sodium Current likely contributes to the formation of conglomerate action potentials in Purkinje neurons.
William A Catterall - One of the best experts on this subject based on the ideXlab platform.
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reduced Sodium Current in purkinje neurons from nav1 1 mutant mice implications for ataxia in severe myoclonic epilepsy in infancy
The Journal of Neuroscience, 2007Co-Authors: Franck Kalume, Ruth E Westenbroek, Frank H. Yu, Todd Scheuer, William A CatterallAbstract:Loss-of-function mutations of Na V 1.1 channels cause severe myoclonic epilepsy in infancy (SMEI), which is accompanied by severe ataxia that contributes substantially to functional impairment and premature deaths. Mutant mice lacking Na V 1.1 channels provide a genetic model for SMEI, exhibiting severe seizures and premature death on postnatal day 15. Behavioral assessment indicated severe motor deficits in mutant mice, including irregularity of stride length during locomotion, impaired motor reflexes in grasping, and mild tremor in limbs when immobile, consistent with cerebellar dysfunction. Immunohistochemical studies showed that Na V 1.1 and Na V 1.6 channels are the primary Sodium channel isoforms expressed in cerebellar Purkinje neurons. The amplitudes of whole-cell peak, persistent, and resurgent Sodium Currents in Purkinje neurons were reduced by 58–69%, without detectable changes in the kinetics or voltage dependence of channel activation or inactivation. Nonlinear loss of Sodium Current in Purkinje neurons from heterozygous and homozygous mutant animals suggested partial compensatory upregulation of Na V 1.6 channel activity. Current-clamp recordings revealed that the firing rates of Purkinje neurons from mutant mice were substantially reduced, with no effect on threshold for action potential generation. Our results show that Na V 1.1 channels play a crucial role in the excitability of cerebellar Purkinje neurons, with major contributions to peak, persistent, and resurgent forms of Sodium Current and to sustained action potential firing. Loss of these channels in Purkinje neurons of mutant mice and SMEI patients may be sufficient to cause their ataxia and related functional deficits.
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reduced Sodium Current in gabaergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
Nature Neuroscience, 2006Co-Authors: Frank H. Yu, Carol A. Robbins, Franck Kalume, Kimberly A. Burton, William J. Spain, Massimo Mantegazza, Ruth E Westenbroek, Todd Scheuer, Stanley G Mcknight, William A CatterallAbstract:Reduced Sodium Current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
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Reduced Sodium Current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
Nature Neuroscience, 2006Co-Authors: Frank H. Yu, Carol A. Robbins, Franck Kalume, Kimberly A. Burton, William J. Spain, G. Stanley Mcknight, Massimo Mantegazza, Ruth E Westenbroek, Todd Scheuer, William A CatterallAbstract:Voltage-gated Sodium channels (Na(V)) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a-/- mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/- mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of Na(V)1.1 did not change voltage-dependent activation or inactivation of Sodium channels in hippocampal neurons. The Sodium Current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/- and Scn1a-/- mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of Na(V)1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced Sodium Currents in GABAergic inhibitory interneurons in Scn1a+/- heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.
Luiz Belardinelli - One of the best experts on this subject based on the ideXlab platform.
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pathophysiology and pharmacology of the cardiac late Sodium Current
Pharmacology & Therapeutics, 2008Co-Authors: Antonio Zaza, Luiz Belardinelli, John C ShryockAbstract:Abstract The “late Sodium Current” (INaL) is a sustained component of the fast Na+ Current of cardiac myocytes and neurons. As recently appreciated, common neurological and cardiac conditions are associated with abnormal INaL enhancement, which may contribute to the pathogenesis of both electrical and contractile dysfunction. For this reason, INaL has become an appealing pharmacological target, with a potentially broad range of therapeutic indications. The recent approval by the FDA of an INaL blocker (ranolazine) for clinical use justifies the increased interest in INaL as a pathogenic mechanism and the rapid evolution of the information concerning it. The review focuses on cardiac aspects of INaL enhancement; it deals with the origin of INaL, with its pathophysiological role and with the consequences of its pharmacological modulation. Both basic aspects and clinical evidence are discussed.
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late Sodium Current inhibition as a new cardioprotective approach
Journal of Molecular and Cellular Cardiology, 2008Co-Authors: Sharon L Hale, John C Shryock, Luiz Belardinelli, Michael O Sweeney, Robert A KlonerAbstract:There is increasing evidence that the late Sodium Current of the Sodium channel in myocytes plays a critical role in the pathophysiology of myocardial ischemia and thus is a potential therapeutic target in patients with ischemic heart disease. Ranolazine, an inhibitor of the late Sodium Current, reduces the frequency and severity of anginal attacks and ST-segment depression in humans, and unlike other antianginal drugs, ranolazine does not alter heart rate or blood pressure. In experimental animal models, ranolazine has been shown to reduce myocardial infarct size and to improve left ventricular function after acute ischemia and chronic heart failure. This article reviews published data describing the role of late Sodium Current and its inhibition by ranolazine in clinical and experimental studies of myocardial ischemia.
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an increase of late Sodium Current induces delayed afterdepolarizations and sustained triggered activity in atrial myocytes
American Journal of Physiology-heart and Circulatory Physiology, 2008Co-Authors: Yejia Song, John C Shryock, Luiz BelardinelliAbstract:This study determined the role of a slowly inactivating component of Sodium Current (INa), late INa, to induce delayed afterdepolarizations (DADs) and triggered activity. We hypothesized that an in...
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inhibition of the late Sodium Current as a potential cardioprotective principle effects of the late Sodium Current inhibitor ranolazine
Heart, 2006Co-Authors: Luiz Belardinelli, John C Shryock, H FraserAbstract:Pathological conditions linked to imbalances in oxygen supply and demand (for example, ischaemia, hypoxia and heart failure) are associated with disruptions in intracellular Sodium ([Na+]i) and calcium ([Ca2+]i) concentration homeostasis of myocardial cells. A decreased efflux or increased influx of Sodium may cause cellular Sodium overload. Sodium overload is followed by an increased influx of calcium through Sodium-calcium exchange. Failure to maintain the homeostasis of [Na+]i and [Ca2+]i leads to electrical instability (arrhythmias), mechanical dysfunction (reduced contractility and increased diastolic tension) and mitochondrial dysfunction. These events increase ATP hydrolysis and decrease ATP formation and, if left uncorrected, they cause cell injury and death. The relative contributions of various pathways (Sodium channels, exchangers and transporters) to the rise in [Na+]i remain a matter of debate. Nevertheless, both the Sodium-hydrogen exchanger and abnormal Sodium channel conductance (that is, increased late Sodium Current (INa)) are likely to contribute to the rise in [Na+]i. The focus of this review is on the role of the late (sustained/persistent) INa in the ionic disturbances associated with ischaemia/hypoxia and heart failure, the consequences of these ionic disturbances, and the cardioprotective effects of the antianginal and anti-ischaemic drug ranolazine. Ranolazine selectively inhibits late INa, reduces [Na+]i-dependent calcium overload and attenuates the abnormalities of ventricular repolarisation and contractility that are associated with ischaemia/reperfusion and heart failure. Thus, inhibition of late INa can reduce [Na+]i-dependent calcium overload and its detrimental effects on myocardial function.
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inhibition of late sustained persistent Sodium Current a potential drug target to reduce intracellular Sodium dependent calcium overload and its detrimental effects on cardiomyocyte function
European Heart Journal Supplements, 2004Co-Authors: Luiz Belardinelli, Charles Antzelevitch, Heather FraserAbstract:This article describes a potential target for therapeutic intervention in ischaemia and heart failure - inhibition of the late (sustained) Sodium Current to reduce the rise in intracellular Sodium and calcium, and to reduce the electrical and mechanical abnormalities associated with these conditions. The new anti-anginal and anti-ischaemic drug ranolazine is a selective inhibitor of the late Sodium Current that is capable of reducing the electrical instability and mechanical dysfunction associated with conditions (e.g. ischaemia, heart failure) known to raise late I N a and [Na + ] i . Because the scope of the review is narrow, many relevant mechanisms involved in the regulation of intracellular Sodium and calcium homeostasis are not discussed, and important individual contributions are not cited. Hence, the reader is referred to more comprehensive reviews of this subject.
Frank H. Yu - One of the best experts on this subject based on the ideXlab platform.
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reduced Sodium Current in purkinje neurons from nav1 1 mutant mice implications for ataxia in severe myoclonic epilepsy in infancy
The Journal of Neuroscience, 2007Co-Authors: Franck Kalume, Ruth E Westenbroek, Frank H. Yu, Todd Scheuer, William A CatterallAbstract:Loss-of-function mutations of Na V 1.1 channels cause severe myoclonic epilepsy in infancy (SMEI), which is accompanied by severe ataxia that contributes substantially to functional impairment and premature deaths. Mutant mice lacking Na V 1.1 channels provide a genetic model for SMEI, exhibiting severe seizures and premature death on postnatal day 15. Behavioral assessment indicated severe motor deficits in mutant mice, including irregularity of stride length during locomotion, impaired motor reflexes in grasping, and mild tremor in limbs when immobile, consistent with cerebellar dysfunction. Immunohistochemical studies showed that Na V 1.1 and Na V 1.6 channels are the primary Sodium channel isoforms expressed in cerebellar Purkinje neurons. The amplitudes of whole-cell peak, persistent, and resurgent Sodium Currents in Purkinje neurons were reduced by 58–69%, without detectable changes in the kinetics or voltage dependence of channel activation or inactivation. Nonlinear loss of Sodium Current in Purkinje neurons from heterozygous and homozygous mutant animals suggested partial compensatory upregulation of Na V 1.6 channel activity. Current-clamp recordings revealed that the firing rates of Purkinje neurons from mutant mice were substantially reduced, with no effect on threshold for action potential generation. Our results show that Na V 1.1 channels play a crucial role in the excitability of cerebellar Purkinje neurons, with major contributions to peak, persistent, and resurgent forms of Sodium Current and to sustained action potential firing. Loss of these channels in Purkinje neurons of mutant mice and SMEI patients may be sufficient to cause their ataxia and related functional deficits.
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reduced Sodium Current in gabaergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
Nature Neuroscience, 2006Co-Authors: Frank H. Yu, Carol A. Robbins, Franck Kalume, Kimberly A. Burton, William J. Spain, Massimo Mantegazza, Ruth E Westenbroek, Todd Scheuer, Stanley G Mcknight, William A CatterallAbstract:Reduced Sodium Current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
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Reduced Sodium Current in GABAergic interneurons in a mouse model of severe myoclonic epilepsy in infancy
Nature Neuroscience, 2006Co-Authors: Frank H. Yu, Carol A. Robbins, Franck Kalume, Kimberly A. Burton, William J. Spain, G. Stanley Mcknight, Massimo Mantegazza, Ruth E Westenbroek, Todd Scheuer, William A CatterallAbstract:Voltage-gated Sodium channels (Na(V)) are critical for initiation of action potentials. Heterozygous loss-of-function mutations in Na(V)1.1 channels cause severe myoclonic epilepsy in infancy (SMEI). Homozygous null Scn1a-/- mice developed ataxia and died on postnatal day (P) 15 but could be sustained to P17.5 with manual feeding. Heterozygous Scn1a+/- mice had spontaneous seizures and sporadic deaths beginning after P21, with a notable dependence on genetic background. Loss of Na(V)1.1 did not change voltage-dependent activation or inactivation of Sodium channels in hippocampal neurons. The Sodium Current density was, however, substantially reduced in inhibitory interneurons of Scn1a+/- and Scn1a-/- mice but not in their excitatory pyramidal neurons. An immunocytochemical survey also showed a specific upregulation of Na(V)1.3 channels in a subset of hippocampal interneurons. Our results indicate that reduced Sodium Currents in GABAergic inhibitory interneurons in Scn1a+/- heterozygotes may cause the hyperexcitability that leads to epilepsy in patients with SMEI.
Enrique Soto - One of the best experts on this subject based on the ideXlab platform.
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the sea anemone bunodosoma caissarum toxin bciii modulates the Sodium Current kinetics of rat dorsal root ganglia neurons and is displaced in a voltage dependent manner
Peptides, 2010Co-Authors: Emilio Salceda, Anoland Garateix, Omar Lopez, Andre Junqueira Zaharenko, Enrique SotoAbstract:Abstract Sea anemone toxins bind to site 3 of the Sodium channels, which is partially formed by the extracellular linker connecting S3 and S4 segments of domain IV, slowing down the inactivation process. In this work we have characterized the actions of BcIII, a sea anemone polypeptide toxin isolated from Bunodosoma caissarum , on neuronal Sodium Currents using the patch clamp technique. Neurons of the dorsal root ganglia of Wistar rats (P5–9) in primary culture were used for this study ( n = 65). The main effects of BcIII were a concentration-dependent increase in the Sodium Current inactivation time course (IC 50 = 2.8 μM) as well as an increase in the Current peak amplitude. BcIII did not modify the voltage at which 50% of the channels are activated or inactivated, nor the reversal potential of Sodium Current. BcIII shows a voltage-dependent action. A progressive acceleration of Sodium Current fast inactivation with longer conditioning pulses was observed, which was steeper as more depolarizing were the prepulses. The same was observed for other two anemone toxins (CgNa, from Condylactis gigantea and ATX-II, from Anemonia viridis ). These results suggest that the binding affinity of sea anemone toxins may be reduced in a voltage-dependent manner, as has been described for α-scorpion toxins.
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The sea anemone toxins BgII and BgIII prolong the inactivation time course of the tetrodotoxin-sensitive Sodium Current in rat dorsal root ganglion neurons.
Journal of Pharmacology and Experimental Therapeutics, 2002Co-Authors: Emilio Salceda, Anoland Garateix, Enrique SotoAbstract:We have characterized the effects of BgII and BgIII, two sea anemone peptides with almost identical sequences (they only differ by a single amino acid), on neuronal Sodium Currents using the whole-cell patch-clamp technique. Neurons of dorsal root ganglia of Wistar rats (P5-9) in primary culture (Leibovitz′s L15 medium; 37°C, 95% air/5% CO2) were used for this study ( n = 154). These cells express two Sodium Current subtypes: tetrodotoxin-sensitive (TTX-S; K i = 0.3 nM) and tetrodotoxin-resistant (TTX-R; K i = 100 μM). Neither BgII nor BgIII had significant effects on TTX-R Sodium Current. Both BgII and BgIII produced a concentration-dependent slowing of the TTX-S Sodium Current inactivation (IC50 = 4.1 ± 1.2 and 11.9 ± 1.4 μM, respectively), with no significant effects on activation time course or Current peak amplitude. For comparison, the concentration-dependent action of Anemonia sulcata toxin II (ATX-II), a well characterized anemone toxin, on the TTX-S Current was also studied. ATX-II also produced a slowing of the TTX-S Sodium Current inactivation, with an IC50 value of 9.6 ± 1.2 μM indicating that BgII was 2.3 times more potent than ATX-II and 2.9 times more potent than BgIII in decreasing the inactivation time constant (τh) of the Sodium Current in dorsal root ganglion neurons. The action of BgIII was voltage-dependent, with significant effects at voltages below −10 mV. Our results suggest that BgII and BgIII affect voltage-gated Sodium channels in a similar fashion to other sea anemone toxins and α-scorpion toxins.
