The Experts below are selected from a list of 159 Experts worldwide ranked by ideXlab platform
Richard A. Baines - One of the best experts on this subject based on the ideXlab platform.
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Regulation of membrane excitability: a convergence on voltage-gated Sodium Conductance
Molecular Neurobiology, 2015Co-Authors: Richard A. BainesAbstract:The voltage-gated Sodium channel (Na_v) plays a key role in regulation of neuronal excitability. Aberrant regulation of Na_v expression and/or function can result in an imbalance in neuronal activity which can progress to epilepsy. Regulation of Na_v activity is achieved by coordination of a multitude of mechanisms including RNA alternative splicing and translational repression. Understanding of these regulatory mechanisms is complicated by extensive genetic redundancy: the mammalian genome encodes ten Na_vs. By contrast, the genome of the fruitfly, Drosophila melanogaster , contains just one Na_v homologue, encoded by paralytic ( DmNa _ v ). Analysis of splicing in DmNa _ v shows variants exhibit distinct gating properties including varying magnitudes of persistent Sodium current (I_NaP). Splicing by Pasilla, an identified RNA splicing factor, alters I_NaP magnitude as part of an activity-dependent mechanism. Enhanced I_NaP promotes membrane hyperexcitability that is associated with seizure-like behaviour in Drosophila . Nova-2, a mammalian Pasilla homologue, has also been linked to splicing of Na_vs and, moreover, mouse gene knockouts display seizure-like behaviour. Expression level of Na_vs is also regulated through a mechanism of translational repression in both flies and mammals. The translational repressor Pumilio (Pum) can bind to Na _ v transcripts and repress the normal process of translation, thus regulating Sodium current (I_Na) density in neurons. Pum2-deficient mice exhibit spontaneous EEG abnormalities. Taken together, aberrant regulation of Na_v function and/or expression is often epileptogenic. As such, a better understanding of regulation of membrane excitability through RNA alternative splicing and translational repression of Na_vs should provide new leads to treat epilepsy.
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regulation of membrane excitability a convergence on voltage gated Sodium Conductance
Molecular Neurobiology, 2015Co-Authors: Richard A. BainesAbstract:The voltage-gated Sodium channel (Nav) plays a key role in regulation of neuronal excitability. Aberrant regulation of Nav expression and/or function can result in an imbalance in neuronal activity which can progress to epilepsy. Regulation of Nav activity is achieved by coordination of a multitude of mechanisms including RNA alternative splicing and translational repression. Understanding of these regulatory mechanisms is complicated by extensive genetic redundancy: the mammalian genome encodes ten Navs. By contrast, the genome of the fruitfly, Drosophila melanogaster, contains just one Nav homologue, encoded by paralytic (DmNav). Analysis of splicing in DmNav shows variants exhibit distinct gating properties including varying magnitudes of persistent Sodium current (INaP). Splicing by Pasilla, an identified RNA splicing factor, alters INaP magnitude as part of an activity-dependent mechanism. Enhanced INaP promotes membrane hyperexcitability that is associated with seizure-like behaviour in Drosophila. Nova-2, a mammalian Pasilla homologue, has also been linked to splicing of Navs and, moreover, mouse gene knockouts display seizure-like behaviour.
T J Obrien - One of the best experts on this subject based on the ideXlab platform.
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properties of an intermediate duration inactivation process of the voltage gated Sodium Conductance in rat hippocampal ca1 neurons
Journal of Neurophysiology, 2016Co-Authors: Christopher A French, Zhen Zeng, David A Williams, Elisa L Hillyardin, T J ObrienAbstract:Rapid transmembrane flow of Sodium ions produces the depolarizing phase of action potentials (APs) in most excitable tissue through voltage-gated Sodium channels (NaV). Macroscopic currents display rapid activation followed by fast inactivation (IF) within milliseconds. Slow inactivation (IS) has been subsequently observed in several preparations including neuronal tissues. IS serves important physiological functions, but the kinetic properties are incompletely characterized, especially the operative timescales. Here we present evidence for an “intermediate inactivation” (II) process in rat hippocampal CA1 neurons with time constants of the order of 100 ms. The half-inactivation potentials ( V 0.5) of steady-state inactivation curves were hyperpolarized by increasing conditioning pulse duration from 50 to 500 ms and could be described by a sum of Boltzmann relations. II state transitions were observed after opening as well as subthreshold potentials. Entry into II after opening was relatively insensitive to membrane potential, and recovery of II became more rapid at hyperpolarized potentials. Removal of fast inactivation with cytoplasmic papaine revealed time constants of I Na decay corresponding to II and IS with long depolarizations. Dynamic clamp revealed attenuation of trains of APs over the 102-ms timescale, suggesting a functional role of II in repetitive firing accommodation. These experimental findings could be reproduced with a five-state Markov model. It is likely that II affects important aspects of hippocampal neuron response and may provide a drug target for Sodium channel modulation.
Jurgen Rettinger - One of the best experts on this subject based on the ideXlab platform.
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novel properties of the depolarization induced endogenous Sodium Conductance in the xenopus laevis oocyte
Pflügers Archiv: European Journal of Physiology, 1999Co-Authors: Jurgen RettingerAbstract:It has been shown by means of the two-microelectrode voltage-clamp technique that in membranes of Xenopus laevis oocytes a Na+-selective permeability can be activated by long-lasting or repetitive depolarization (R.T. Kado and C. Baud, Journal of Physiology, Paris, 77:1113–1117, 1981). In this study the permeability in inside-out giant membrane patches with diameters of 20–30 µm was analysed. Once induced, the Na+ permeability has a voltage-dependent open probability that increases with positive potentials and half-maximally activates at about 0 mV. Sudden changes of membrane potential elicit transient currents with strongly voltage-dependent time constants of from less than 1 ms at –150 mV to several hundreds of milliseconds at positive potentials. In contrast to the on-cell configuration, the permeability ceases completely within a few minutes in the cell-free inside-out configuration. This rundown can be prevented by including MgATP, but not Mg2+ or ATP alone, in the intracellular solution. Intracellular Mg2+ ions, in addition to being a co-factor for ATP in the activation process, decrease the permeability in a dose-dependent manner. Steady-state fluctuation analysis gave no evidence that an increased noise level is caused by open–close kinetics of an ion channel, suggesting that the single-channel Conductance is below 1 pS if a channel-like structure is the origin of the endogenous Na+ permeability.
Christopher A French - One of the best experts on this subject based on the ideXlab platform.
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properties of an intermediate duration inactivation process of the voltage gated Sodium Conductance in rat hippocampal ca1 neurons
Journal of Neurophysiology, 2016Co-Authors: Christopher A French, Zhen Zeng, David A Williams, Elisa L Hillyardin, T J ObrienAbstract:Rapid transmembrane flow of Sodium ions produces the depolarizing phase of action potentials (APs) in most excitable tissue through voltage-gated Sodium channels (NaV). Macroscopic currents display rapid activation followed by fast inactivation (IF) within milliseconds. Slow inactivation (IS) has been subsequently observed in several preparations including neuronal tissues. IS serves important physiological functions, but the kinetic properties are incompletely characterized, especially the operative timescales. Here we present evidence for an “intermediate inactivation” (II) process in rat hippocampal CA1 neurons with time constants of the order of 100 ms. The half-inactivation potentials ( V 0.5) of steady-state inactivation curves were hyperpolarized by increasing conditioning pulse duration from 50 to 500 ms and could be described by a sum of Boltzmann relations. II state transitions were observed after opening as well as subthreshold potentials. Entry into II after opening was relatively insensitive to membrane potential, and recovery of II became more rapid at hyperpolarized potentials. Removal of fast inactivation with cytoplasmic papaine revealed time constants of I Na decay corresponding to II and IS with long depolarizations. Dynamic clamp revealed attenuation of trains of APs over the 102-ms timescale, suggesting a functional role of II in repetitive firing accommodation. These experimental findings could be reproduced with a five-state Markov model. It is likely that II affects important aspects of hippocampal neuron response and may provide a drug target for Sodium channel modulation.
Eve Marder - One of the best experts on this subject based on the ideXlab platform.
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increase in Sodium Conductance decreases firing rate and gain in model neurons
The Journal of Neuroscience, 2012Co-Authors: Tilman J Kispersky, Jonathan S Caplan, Eve MarderAbstract:We studied the effects of increased Sodium Conductance on firing rate and gain in two populations of Conductance-based, single-compartment model neurons. The first population consisted of 1000 model neurons with differing values of seven voltage-dependent Conductances. In many of these models, increasing the Sodium Conductance three-fold unexpectedly reduced the firing rate and divisively scaled the gain at high input current. In the second population, consisting of 1000 simplified model neurons, we found that enhanced Sodium Conductance changed the frequency-current (FI) curve in two computationally distinct ways, depending on the firing rate. In these models, increased Sodium Conductance produced a subtractive shift in the FI curve at low firing rates because the additional Sodium Conductance allowed the neuron to respond more strongly to equivalent input current. In contrast, at high input current, the increase in Sodium Conductance resulted in a divisive change in the gain because the increased Conductance produced a proportionally larger activation of the delayed rectifier potassium Conductance. The control and Sodium-enhanced FI curves intersect at a point that delimits two regions in which the same biophysical manipulation produces two fundamentally different changes to the model neuron's computational properties. This suggests a potentially difficult problem for homeostatic regulation of intrinsic excitability.