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PubMed1989

Two molecular transitions influence cardiac sodium channel gating.

Sodium channels from diverse excitable membranes are very similar in their structure, yet surprisingly heterogeneous in their behavior. The processes that govern the opening and closing of sodium channels have appeared difficult to describe in terms of a single, unifying molecular scheme. Now cardiac sodium channels have been analyzed by high-resolution single-channel recordings over a broad range of potentials. Channels exhibited both complex and simple gating patterns at different voltages. Such behavioral diversity can be explained by the balance between two molecular transitions whereby channels can exit the open state.

Electric Conductivity↗
PubMed1998

The effects of propofol on macroscopic and single channel sodium currents in rat ventricular myocytes.

1. The effects of the injectable anaesthetic agent propofol (di-isopropyl phenol) were examined on sodium currents and single sodium channels by use of patch-clamp techniques in ventricular myocytes isolated from rat hearts. 2. Propofol dose-dependently blocked the whole cell sodium currents evoked by a voltage step to -30 mV from a holding potential of -90 mV with an EC50 of 14.8+/-2.3 microM (mean+/-s.e.mean). 3. Propofol caused a substantial hyperpolarizing shift in the voltage-dependence of inactivation of sodium currents (168 microM (30 microg ml(-1)) propofol caused a -14 mV shift (P<0.01); 56 microM caused a -8 mV shift (P<0.05)). A smaller shift in the voltage-dependence of activation was produced (4 mV by 168 microM (not statistically significant)), but this was to more depolarized potentials. The maximal sodium conductance, as judged from the activation and inactivation curves, was reduced by 13% by 168 microM propofol (not statistically significant), but propofol did not affect the reversal potential of the current-voltage relationship. 4. The macroscopic rate of inactivation, as measured by the time constant of the exponential fall of current amplitude from the peak current, was also slowed by propofol, from a control time constant of 1.78+/-0.31 ms to 2.93+/-0.47 ms (mean+/-s.e.mean, n=8, P<0.05) by 168 microM propofol. Despite the increase in the time constant, the macroscopic inactivation remained well fitted by a single exponential. The macroscopic rate of activation was also slowed, but to a lesser degree (<10%, not statistically significant) by 168 microM propofol. 5. Propofol slowed the rate of recovery from inactivation of the sodium current, as measured by a two pulse protocol. Propofol (168 microM) increased the time constant of recovery, measured at -100 mV and room temperature, from a control value of 55+/-5.9 ms to 141+/-24.2 ms (mean+/-s.e.mean, n=8, P<0.01). Although the time constant was increased at all voltages measured, the intrinsic voltage-dependence of the rate of recovery was not changed. 6. Single channel recordings showed that the mean open time of single sodium channels was dramatically reduced by propofol (from 0.50+/-0.02 ms in control to 0.28+/-0.01 ms by 56 +/-M propofol and to 0.24+/-0.01 ms by 168 microM, both significantly different from control, P<0.01). Single channel conductance was not changed by either concentration of propofol.

Anesthetics, Intravenous↗
PubMed1992

The sodium channel activator Brevetoxin-3 uncovers a multiplicity of different open states of the cardiac sodium channel.

The interaction of Brevetoxin 3 (Pbtx-3), a sodium channel activator, with the cardiac sodium channel was studied at the single channel level. It was found that Pbtx-3 (20 microM) shifted steady-state activation to negative potentials, without major effects on the time course of macroscopic activation or macroscopic currents decay, as calculated from averaged single-channel records. Single-channel open times were found to be prolonged. Under the influence of the toxin, sodium channel openings could be observed frequently even at maintained depolarisation. These openings occurred to at least nine different subconductance levels of the open state with smaller conductivities than the maximal one and differed in their open times. Current amplitudes of these open substates were found to cluster around certain amplitude values. Appearance of substates at maintained depolarisation was dependent on the transmembrane potential (Em): Substates with smaller conductivity appeared more frequently at lower Em values whereas at higher Em values substates with higher conductivity values dominated. Furthermore, it was demonstrated that appearance of substates did not result from incomplete recovery from inactivation. From these observations it was concluded that the open substates observed correspond to different conformational states of the channel's activation gates. Under physiological conditions, when the sodium channel opens directly from its closed state these 'incomplete'-open states of the cardiac sodium channel are obscured by fast gating transitions between the corresponding, electrically silent, preopen states. Thus, Pbtx-3 acts mainly via stabilisation of the channel's preopen and different open states. A classification of sodium channel modifiers, based on their interaction with different conformational states of the channel is suggested.

Animals↗
PubMed1981

Barbiturates: active form and site of action at node of Ranvier sodium channels.

Barbiturate sodium channel block was investigated in the voltage-clamped amphibian node of Ranvier. Internal pH was manipulated by diffusion of buffers from the cut internodes. Like local anesthetics and volatile general anesthetics, barbiturates shift the voltage dependence of inactivation in the hyperpolarizing direction. A barbiturate anion, 5-phenyl barbituric acid, blocks sodium channels when applied externally or internally. On external application, block is of very slow onset. The barbiturate anion, like the local anesthetic cation, thus appears to bind to a receptor site on the axoplasmic side of the membrane. Unlike local anesthetics, however, phenobarbital exerts a frequency-dependent block which is modified by changes in internal pH and is not affected by changes in external pH. In addition, barbiturate frequency dependence is apparently more exclusively involved with channel inactivation. The results suggest a barbiturate sodium channel binding site closer to the axoplasm than the local anesthetic binding site is and also suggest that there is a proton barrier between the two sites.

Animals↗
PubMed1993

Modulation of flecainide's cardiac sodium channel blocking actions by extracellular sodium: a possible cellular mechanism for the action of sodium salts in flecainide cardiotoxicity.

Sodium salts reverse the clinical cardiotoxicity of class 1c antiarrhythmic agents, but the underlying mechanisms are unknown. We studied the modulation of flecainide's action by changes in extracellular sodium concentration ([Na+]e) produced by isotonic substitution of choline for sodium. Increasing [Na+]e by 25 mM attenuated the depressant effects of 3.2 microM flecainide of Vmax in canine cardiac Purkinje fibers, whereas decreasing [Na+]e enhanced drug action. The voltage dependence of Vmax was shifted by flecainide (activation potential for 50% decrease in Vmax, V50: -77.4 +/- 3.5 mV at 3.2 microM flecainide) compared to control (V50: -73.7 +/- 2.8 mV, mean +/- S.D., P < .05). Increasing [Na+]e in the presence of flecainide returned V50 toward control (-75.8 +/- 3.1 mV, P < .05 vs. flecainide at normal [Na+]e). Increased [Na+]e shifted the flecainide concentration-response curve to the right (EC50 19.0 microM) compared to normal (EC50 14.6 microM) and low (EC50 10.8 microM) [Na+]e. [Na+]e modulated the concentration-dependent displacement by flecainide of [3H]batrachotoxin-A-benzoate, with increased [Na+]e shifting the binding curve to the right and decreased [Na+]e shifting it to the left compared to normal [Na+]e. There was a strong linear correlation (r = 0.99) between flecainide's EC50 for Vmax depression and its IC50 for [3H]batrachotoxin-A-benzoate displacement at various [Na+]e. We conclude that [Na+]e modulates flecainide's interaction with the sodium channel. Sodium's ability to displace blocking drug from the sodium channel may underlie the efficacy of sodium salts in treating flecainide toxicity, and could play a similar role in antagonizing cardiotoxicity of other class 1 compounds.

Action Potentials↗
PubMed2002

Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits.

Sodium channel beta-subunits modulate channel gating, assembly, and cell surface expression in heterologous cell systems. We generated beta2(-/-) mice to investigate the role of beta2 in control of sodium channel density, localization, and function in neurons in vivo. Measurements of [(3)H]saxitoxin (STX) binding showed a significant reduction in the level of plasma membrane sodium channels in beta2(-/-) neurons. The loss of beta2 resulted in negative shifts in the voltage dependence of inactivation as well as significant decreases in sodium current density in acutely dissociated hippocampal neurons. The integral of the compound action potential in optic nerve was significantly reduced, and the threshold for action potential generation was increased, indicating a reduction in the level of functional plasma membrane sodium channels. In contrast, the conduction velocity, the number and size of axons in the optic nerve, and the specific localization of Na(v)1.6 channels in the nodes of Ranvier were unchanged. beta2(-/-) mice displayed increased susceptibility to seizures, as indicated by reduced latency and threshold for pilocarpine-induced seizures, but seemed normal in other neurological tests. Our observations show that beta2-subunits play an important role in the regulation of sodium channel density and function in neurons in vivo and are required for normal action potential generation and control of excitability.

Action Potentials↗
PubMed1988

Effects of dihydropyridine calcium channel modulators on cardiac sodium channels.

To investigate whether cardiac sodium channels have dihydropyridine (DHP) receptors we studied the effects of the optically pure (greater than 95%) enantiomers of the DHPs PN200-110 and BAY-K 8644 and the racemic DHP nitrendipine (NTD). Whole cell and single-channel sodium currents were recorded from cultured ventricular cells of neonatal rats using the patch-clamp method. NTD reduced cardiac sodium currents in a voltage-dependent manner. Inhibitory effects were due to an increase in traces without activity. The unit conductance remained unchanged. At negative holding potentials, NTD transiently increased the probability of channel opening. Both (+) and (-) PN 200-110 blocked sodium channels, although the (-) isomer was about one order of magnitude less effective. The blocking effects were voltage dependent. (+) BAY-K 8644 had similar blocking effects. (-) BAY-K 8644 produced an increase in sodium currents due to an increased frequency of channel openings and a marked prolongation of open time without any significant change in unit conductance. The DHPs have effects on cardiac sodium whole cell and single-channel currents that appear identical to and are as stereospecific as their effects on cardiac calcium currents, although the concentrations required are larger. In contrast the inwardly rectifying potassium channel (IK1) is unaffected by these DHPs. We conclude that functionally equivalent DHP receptors are present in cardiac sodium and calcium channels but not potassium channels and take this as evidence of the homology between sodium and calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2006

Sodium channel beta2 subunits regulate tetrodotoxin-sensitive sodium channels in small dorsal root ganglion neurons and modulate the response to pain.

Voltage-gated sodium channel (Na(v)1) beta2 subunits modulate channel gating, assembly, and cell-surface expression in CNS neurons in vitro and in vivo. beta2 expression increases in sensory neurons after nerve injury, and development of mechanical allodynia in the spared nerve injury model is attenuated in beta2-null mice. Thus, we hypothesized that beta2 modulates electrical excitability in dorsal root ganglion (DRG) neurons in vivo. We compared sodium currents (I(Na)) in small DRG neurons from beta2+/+ and beta2-/- mice to determine the effects of beta2 on tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na(v)1 in vivo. Small-fast DRG neurons acutely isolated from beta2-/- mice showed significant decreases in TTX-S I(Na) compared with beta2+/+ neurons. This decrease included a 51% reduction in maximal sodium conductance with no detectable changes in the voltage dependence of activation or inactivation. TTX-S, but not TTX-R, I(Na) activation and inactivation kinetics in these cells were slower in beta2(-/-) mice compared with controls. The selective regulation of TTX-S I(Na) was supported by reductions in transcript and protein levels of TTX-S Na(v)1s, particularly Na(v)1.7. Low-threshold mechanical sensitivity was preserved in beta2-/- mice, but they were more sensitive to noxious thermal stimuli than wild type whereas their response during the late phase of the formalin test was attenuated. Our results suggest that beta2 modulates TTX-S Na(v)1 mRNA and protein expression resulting in increased TTX-S I(Na) and increases the rates of TTX-S Na(v)1 activation and inactivation in small-fast DRG neurons in vivo. TTX-R I(Na) were not significantly modulated by beta2.

Adaptation, Physiological↗
PubMed1997

A reappraisal of aldosterone effects on the kidney: new insights provided by epithelial sodium channel cloning.

Sodium homeostasis is crucial for the control of extra-cellular volume and blood pressure. Regulation of sodium reabsorption is mainly achieved in the distal nephron by the mineralocorticoid aldosterone, but the molecular pathway of aldosterone action has largely remained unclear. Molecular genetic analysis of inherited diseases disturbing sodium homeostasis has now demonstrated that the amiloride-sensitive epithelial sodium channel is a major effector of aldosterone action. Mechanisms by which aldosterone regulates the epithelial sodium channel activity are beginning to emerge and will be of great importance for a better understanding of salt-sensitive hypertension.

Aldosterone↗
PubMed2003

The sodium channel blocker RS100642 reverses down-regulation of the sodium channel alpha-subunit Na(v) 1.1 expression caused by transient ischemic brain injury in rats.

In this study we evaluated the expression of five sodium channel (NaCh) Alpha-subunit genes after transient middle cerebral artery occlusion (MCAo) in the rat and the effects of treatment with the NaCh blocker and experimental neuroprotective agent RS100642 as compared to the prototype NaCh blocker mexiletine. The expression of Na(v) 1.1, Na(v) 1.2, Na(v) 1.3, Na(v) 1.7, Na(v) 1.8 and the housekeeping gene beta-actin were studied in vehicle or drug-treated rats at 6, 24 and 48 h post-MCAo using real-time quantitative RT-PCR. RS100642 (1 mg/kg), mexiletine (10 mg/kg), or vehicle (1 ml/kg) was injected (i.v.) at 30 min, 2, 4, and 6 h post-injury. Following MCAo only the Na(v) 1.1 and Na(v) 1.2 genes were significantly down-regulated in the ipsilateral hemisphere of the injured brains. RS100642 treatment significantly reversed the down-regulation of Na(v) 1.1 (but not Na(v) 1.2) at 24-48 h post-injury. Mexiletine treatment, on the other hand, had no significant effect on the down-regulation of either gene. These findings demonstrate that treatment with a neuroprotective dose of RS100642 significantly reverses the down-regulation of Na(v) 1.1 caused by ischemic brain injury and suggests that RS100642 selectively targets the Na(v) 1.1 Alpha-subunit of the NaCh. Furthermore, our findings strengthen the hypothesis that ischemic injury may produce selective depletion of voltage-gated NaChs, and suggest that the Na(v) 1.1 NaCh Alpha-subunit may play a key role in the neuronal injury/recovery process.

Animals↗
PubMed2003

Down regulation of sodium channel Na(v)1.1 expression by veratridine and its reversal by a novel sodium channel blocker, RS100642, in primary neuronal cultures.

This study investigated the effects of veratridine-induced neuronal toxicity on sodium channel gene (NaCh) expression in primary forebrain cultures enriched in neurons, and its reversal by a novel sodium channel blocker, RS100642. Using quantitative RT-PCR, our findings demonstrated the expression ratio of NaCh genes in normal fetal rat forebrain neurons to be Na(v)1.2 > Na(v)1.3 > Na(v)1.8 > Na(v)1.1 > Na(v)1.7 (rBII > rBIII > PN3 > rBI > PN1). Veratridine treatment of neuronal cells produced neurotoxicity in a dose-dependent manner (0.25-20 micro M). Neuronal injury caused by a dose of veratridine producing 80% cell death (2.5 micro M) significantly, and exclusively down-regulated the Na(v)1.1 gene. However, treatment of neurons with RS100642 (200 micro M) reversed the down-regulation of the Na(v)1.1 gene expression caused by veratridine. Our findings document for the first time quantitative and relative changes in the expression of various NaCh genes in neurons following injury produced by selective activation of voltage-gated sodium channels, and suggest that the Na(v)1.1 sodium channel gene may play a key role in the neuronal injury/recovery process.

Animals↗
PubMed1996

The beta 1 sodium channel subunit modifies the interactions of neurotoxins and local anesthetics with the rat brain IIA alpha sodium channel in isolated membranes but not in intact cells.

Mammalian brain sodium channels consist of an alpha subunit and two smaller beta subunits. The role of the beta 1 subunit in modulating ligand interactions at these channels was examined using a cell line stably expressing human beta1 and rat brain IIA alpha subunits. Coexpression of the beta 1 subunit had no effect on the potencies of sodium channel blockers in inhibiting whole cell [3H]batrachotoxinin A benzoate ([3H]BTX) binding or veratridine-stimulated [14C]guanidinium influx. Coexpression of the beta 1 subunit also had no effect on the potencies of alpha scorpion toxin, brevetoxin, or RU 39568 in stimulating [14C]guanidinium influx. By contrast, coexpression of the beta 1 subunit had dramatic effects on ligand interactions in isolated membranes. In isolated membranes of cells expressing only the alpha subunit, the neurotoxins had no stimulatory effect on [3H]BTX binding and the potencies of local anesthetic-like channel inhibitors were 10-100-fold lower than those at native sodium channels. Whereas in membranes of cells coexpressing the beta 1 subunit, the neurotoxins increased [3H]BTX binding 30-fold and the potencies of the sodium channel inhibitors closely matched those found at native sodium channels. These findings indicate that the beta 1 subunit is not required for the binding of sodium channel activators or inhibitors but rather, that the beta 1 subunit may stabilize the alpha subunit in a functional conformation thereby allowing detection of these interactions in disrupted membranes.

Anesthetics, Local↗
PubMed1986

Membrane potentials and sodium channels: hypotheses for growth regulation and cancer formation based on changes in sodium channels and gap junctions.

Based on several convergent lines of investigation, we make two hypotheses which are sufficient to explain many phenomena of growth regulation in both normal and cancer cells. 1. The first hypothesis is that there is a boundary or threshold of resting cell membrane potential that separates normal resting cells from normal proliferating cells and cancer cells. The basis for this in existing literature values of membrane potentials in resting and proliferating cells is established. A discussion of how these differences in potential can be explained focuses on changes in sodium permeability and internal sodium concentration. Of many sodium transfer mechanisms, the sodium channel is emphasized and how increased intracellular transfer may stimulate DNA synthesis. The effects of changing cell junctions, in particular gap junctions, on membrane potentials is also discussed, as well as the indications of altered junctions in tumor cells. The linking factor of the effects of growth factors on both cell junctions and sodium permeability leads to the second hypothesis. 2. Since growth initiation and inhibition involve sodium channels and gap junctions, several phenomena can be explained by postulating that they are one and the same entity. The basis for this hypothesis in existing descriptions of functional and structural similarities is outlined. The possible interchange of these elements in the cell cycle lead to several corollaries consequent to the conservation of their total number. The formation of gap junctions would consume sodium channels, decrease sodium permeability and stop DNA synthesis. Conversely, growth factors may competitively bind to channel-connexon elements, cleave gap junctions, liberate sodium channels to increase sodium permeability, and trigger DNA synthesis. Alterations in the structure of gap junction-channel elements in tumor cells would be sufficient to explain some carcinogenesis.

Cell Cycle↗
PubMed1996

Relative role of alkalosis and sodium ions in reversal of class I antiarrhythmic drug-induced sodium channel blockade by sodium bicarbonate.

BACKGROUND: Hypertonic sodium salts are used to treat sodium channel-blocking drug cardiotoxicity. The relative roles of alkalinization and increased sodium concentration ([Na+]o) for various drugs are incompletely known. METHODS AND RESULTS: The effects of four class I drugs on action potential characteristics of canine Purkinje fibers at equieffective concentrations (disopyramide 30 mumol/L, mexiletine 80 mumol/L, flecainide 7 mumol/L, imipramine 5 mumol/L) were studied in the presence of normal Tyrode solution and one altered solution (increased [Na+]o, increased bicarbonate concentration, or both) in each experiment. Combined increases in sodium and bicarbonate concentration significantly reduced the depressant effects of flecainide, imipramine, and mexiletine on phase 0 upstroke (Vmax) but did not alter the effects of disopyramide. The effects of sodium bicarbonate were entirely due to alkalinization in the case of imipramine, but both alkalinization and increased [Na+]o contributed to the interaction with flecainide and mexiletine. The reversal of Vmax depression by increased [Na+]o and pH was due in part to hyperpolarization. In addition, alkalosis directly reversed the hyperpolarizing shift in Vmax inactivation caused by flecainide and imipramine without altering the shift caused by disopyramide and mexiletine. CONCLUSIONS: Increases in sodium bicarbonate concentration reverse the effects of class I antiarrhythmic drugs to a varying extent, with drug-specific contributions of the sodium and bicarbonate moiety. The molecular basis for this drug specificity remains to be elucidated, but it has important potential implications for the use of hypertonic sodium salts to treat cardiotoxicity caused by sodium channel-blocking drugs.

Alkalosis↗
PubMed1992

Calcium channel characteristics conferred on the sodium channel by single mutations.

The sodium channel, one of the family of structurally homologous voltage-gated ion channels, differs from other members, such as the calcium and the potassium channels, in its high selectivity for Na+. This selectivity presumably reflects a distinct structure of its ion-conducting pore. We have recently identified two clusters of predominantly negatively charged amino-acid residues, located at equivalent positions in the four internal repeats of the sodium channel as the main determinants of sensitivity to the blockers tetrodotoxin and saxitoxin. All site-directed mutations reducing net negative charge at these positions also caused a marked decrease in single-channel conductance. Thus these two amino-acid clusters probably form part of the extracellular mouth and/or the pore wall of the sodium channel. We report here the effects on ion selectivity of replacing lysine at position 1,422 in repeat III and/or alanine at position 1,714 in repeat IV of rat sodium channel II (ref. 3), each located in one of the two clusters, by glutamic acid, which occurs at the equivalent positions in calcium channels. These amino-acid substitutions, unlike other substitutions in the adjacent regions, alter ion-selection properties of the sodium channel to resemble those of calcium channels. This result indicates that lysine 1,422 and alanine 1,714 are critical in determining the ion selectivity of the sodium channel, suggesting that these residues constitute part of the selectivity filter of the channel.

Amino Acid Sequence↗
PubMed2002

Cystic fibrosis transmembrane conductance regulator-dependent up-regulation of Kir1.1 (ROMK) renal K+ channels by the epithelial sodium channel.

The epithelial sodium channel (ENaC) and the secretory potassium channel (Kir1.1/ROMK) are expressed in the apical membrane of renal collecting duct principal cells where they provide the rate-limiting steps for Na(+) absorption and K(+) secretion. The cystic fibrosis transmembrane conductance regulator (CFTR) is thought to regulate the function of both ENaC and Kir1.1. We hypothesized that CFTR may provide a regulatory link between ENaC and Kir1.1. In Xenopus laevis oocytes co-expressing both ENaC and CFTR, the CFTR currents were 3-fold larger than those in oocytes expressing CFTR alone due to an increased expression of CFTR in the plasma membrane. ENaC was also able to increase Kir1.1 currents through an increase in surface expression, but only in the presence of CFTR. In the absence of CFTR, co-expression of ENaC was without effect on Kir1.1. ENaC-mediated CFTR-dependent up-regulation of Kir1.1 was reduced with a Liddle's syndrome mutant of ENaC. Furthermore, ENaC co-expressed with CFTR was without effect on the closely related K(+) channel, Kir4.1. We conclude that ENaC up-regulates Kir1.1 in a CFTR-dependent manner. CFTR may therefore provide the mechanistic link that mediates the coordinated up-regulation of Kir1.1 during the stimulation of ENaC by hormones such as aldosterone or antidiuretic hormone.

Aldosterone↗
PubMed1999

Mutations in the house fly Vssc1 sodium channel gene associated with super-kdr resistance abolish the pyrethroid sensitivity of Vssc1/tipE sodium channels expressed in Xenopus oocytes.

The super-kdr insecticide resistance trait of the house fly confers resistance to pyrethroids and DDT by reducing the sensitivity of the fly nervous system. The super-kdr genetic locus is tightly linked to the Vssc1 gene, which encodes a voltage-sensitive sodium channel alpha subunit that is the principal site of pyrethroid action. DNA sequence analysis of Vssc1 alleles from several independent super-kdr fly strains identified two amino acid substitutions associated with the super-kdr trait: replacement of leucine at position 1014 with phenylalanine (L1014F), which has been shown to cause the kdr resistance trait in this species, and replacement of methionine at position 918 with threonine (M918T). We examined the functional significance of these mutations by expressing house fly sodium channels containing them in Xenopus laevis oocytes and by characterizing the biophysical properties and pyrethroid sensitivities of the expressed channels using two-electrode voltage clamp. House fly sodium channels that were specifically modified by site-directed mutagenesis to contain the M918T/L1014F double mutation gave reduced levels of sodium current expression in oocytes but otherwise exhibited functional properties similar to those of wildtype channels and channels containing the L1014F substitution. However, M918T/L1014F channels were completely insensitive to high concentrations of the pyrethroids cismethrin and cypermethrin. House fly sodium channels specifically modified to contain the M918T single mutation, which is not known to exist in nature except in association with the L1014F mutation, gave very small sodium currents in oocytes. Assays of these currents in the presence of high concentrations of cismethrin suggest that this mutation alone is sufficient to abolish the pyrethroid sensitivity of house fly sodium channels. These results define the functional significance of the Vssc1 mutations associated with the super-kdr trait of the house fly and are consistent with the hypothesis that the super-kdr trait arose by selection of a second-site mutation (M918T) that confers to flies possessing it even greater resistance than the kdr allele containing the L1014F mutation.

Animals↗
PubMed2000

Selective depression of low-release probability excitatory synapses by sodium channel blockers.

Sodium channels (NaChs) play a central role in action potential generation and are uniquely poised to influence the efficacy of transmitter release. We evaluated the effect of partial NaCh blockade on two aspects of synaptic efficacy First, we evaluated whether NaCh blockade accounts for the ability of certain drugs to selectively depress glutamate release. Second, we evaluated the contribution of NaChs to intraneuronal variability in glutamate release probability (p(r)). The antiglutamate drug riluzole nearly completely depresses glutamate excitatory postsynaptic currents (EPSCs) at concentrations that barely affect GABAergic inhibitory postsynaptic currents (IPSCs). NaCh inhibition explains the selective depression. Unlike other presynaptic depressants, partial NaCh blockade increases paired-pulse EPSC depression. This result is explained by selective depression of low-p(r) synapses. We conclude that local variations in the action potential contribute to p(r) variability among excitatory synapses.

Action Potentials↗