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PubMed2006

GABA(B) receptors inhibit backpropagating dendritic spikes in hippocampal CA1 pyramidal cells in vivo.

Spike backpropagation has been proposed to enhance dendritic depolarization and synaptic plasticity. However, relatively little is known about the inhibitory control of spike backpropagation in vivo. In this study, the backpropagation of the antidromic spike into the dendrites of CA1 pyramidal cells was studied by extracellular recording in urethane-anesthetized rats. The population antidromic spike (pAS) in CA1 following stimulation of the alveus was recorded simultaneously with a 16-channel silicon probe and analyzed as current source density (CSD). The pAS current sink was shown to sequentially invade the soma and then the apical and basal dendrites. When the pAS was preceded <400 ms by a conditioning orthodromic CA3 stimulus, the apical and basal dendritic spike sinks were reduced and delayed. Dendritic spike suppression was large after a high-intensity CA3 conditioning stimulus that evoked a population spike, small after a low-intensity CA3 conditioning stimulus, and weak after conditioning by another pAS. The late (150-400 ms latency) inhibition of the backpropagating pAS at the apical and basal dendrites was partially relieved by a GABA(B) receptor antagonist, CGP35348 or CGP56999A, given intracerebroventricularly (icv). CGP35348 icv also decreased the latency of the antidromic spike sinks at all depths. A compartment cable model of a CA1 pyramidal cell with excitable dendrites, combined with a model of extracellular potential generation, confirms that GABA(B) receptor activation delays a backpropagating spike and blocks distal dendritic spikes. GABA(B) receptor-mediated conductance increase and hyperpolarization, amplified by removing dendritic I(A) inactivation, contribute to conditioned dendritic spike suppression. In addition, the model shows that slow Na(+) channel inactivation also participates in conditioned spike suppression, which may partly explain the small dendritic spike suppression after conditioning with a weak orthodromic stimulus or another antidromic spike. Thus, both theory and experiment confirm an important role of the GABA(B) receptors in controlling dendritic spike backpropagation.

Animals↗
PubMed2007

Evidence for a critical role of entorhinal cortex at pre-exposure for latent inhibition disruption in rats.

Latent inhibition (LI), that is the decrease in conditioned response induced by the repeated nonreinforced pre-exposures to the to-be-conditioned stimulus, is disrupted by entorhinal cortex (EC) lesions. The mechanism involved in this disruption is unknown, and in particular the experimental stage (pre-exposure or conditioning) at which the integrity of EC is necessary has to be determined. The purpose of this study was to address this issue by using reversible inactivation of the EC by local micro-infusion of tetrodotoxin (TTX). TTX was infused either before the pre-exposure phase, before the conditioning phase, or before both phases. LI was unaffected in rats that received TTX before conditioning or before both pre-exposure and conditioning. In contrast, LI was disrupted in rats that received TTX before pre-exposure only. These results are discussed in the framework of LI models.

Animals↗
PubMed2003

Contribution of functional voltage-gated Na+ channel expression to cell behaviors involved in the metastatic cascade in rat prostate cancer: II. Secretory membrane activity.

The secretory membrane activities of two rat prostate cancer cell lines of markedly different metastatic potential, and corresponding electrophysiological characteristics, were studied in a comparative approach. In particular, voltage-gated Na(+) channels (VGSCs) were expressed in the strongly metastatic MAT-LyLu but not in the closely related, but weakly metastatic, AT-2 cells. Uptake and release of the non-cytotoxic marker horseradish peroxidase (HRP) were used as indices of general endocytotic and exocytotic membrane activity, respectively. The amount of tracer present in a given experimental condition was quantified by light microscopic digital imaging. The uptake of HRP was an active process, abolished completely by incubating the cells at low temperature (5 degrees C) and suppressed by disrupting the cytoskeleton. Interestingly, the extent of HRP uptake into the strongly metastatic MAT-LyLu cells was almost twice that into the weakly metastatic AT-2 cells. Vesicular uptake of HRP occurred in a fast followed by a slow phase; these appeared to correspond to cytoplasmic and perinuclear pools, respectively. Importantly, the overall quantitative difference in the uptake disappeared in the presence of 1 microM tetrodotoxin which significantly reduced the uptake of HRP into the MAT-LyLu cells. There was no effect on the AT-2 cells, consistent with functional VGSC expression occurring selectively in the former. A similar effect was observed in Na(+)-free medium. The uptake was partially dependent upon extracellular Ca(2+) but was not affected by raising the extracellular K(+) concentration. We suggest that functional VGSC expression could potentiate prostate cancer cells' metastatic ability by enhancing their secretory membrane activity.

Animals↗
PubMed2007

Functional expression of voltage-gated sodium channels in primary cultures of human cervical cancer.

Cervical cancer (CaC) is the third most frequent cause of death from cancer among women in the world and the first in females of developing countries. Several ion channels are upregulated in cancer, actually potassium channels have been suggested as tumor markers and therapeutic targets for CaC. Voltage-gated sodium channels (VGSC) activity is involved in proliferation, motility, and invasion of prostate and breast cancer cells; however, the participation of this type of channels in CaC has not been explored. In the present study, we identified both at the molecular and electrophysiological level VGSC in primary cultures from human cervical carcinoma biopsies. With the whole cell patch clamp technique, we isolated and identified a voltage-gated Na(+) current as the main component of the inward current in all investigated cells. Sodium current was characterized by its kinetics, voltage dependence, sensitivity to tetrodotoxin (TTX) block and dependence to [Na(+)](o). By analyzing the expression of mRNAs encoding TTX-sensitive Na(+) channel alpha subunits with standard RT-PCR and specific primers, we detected Na(v)1.2, Na(v)1.4, Na(v)1.6, and Na(v)1.7 transcripts in total RNA obtained from primary cultures and biopsies of CaC. Restriction enzyme analysis of PCR products was consistent with the molecular nature of the corresponding genes. Notably, only transcripts for Na(v)1.4 sodium channels were detected in biopsies from normal cervix. The results show for the first time the functional expression of VGSC in primary cultures from human CaC, and suggest that these channels might be considered as potential molecular markers for this type of cancer.

Biomarkers, Tumor↗
PubMed2002

Interaction of high concentrations of riluzole with recombinant skeletal muscle sodium channels and adult-type nicotinic receptor channels.

Riluzole is a neuroprotective drug that modulates glutamergic transmission but also blocks the inactivated state of voltage-gated neuronal sodium channels at very low concentrations (about 0.1 microM). After nausea, the most common adverse effect of riluzole is asthenia, which could be due to a block of muscle sodium channels or acetylcholine receptor channels. Using the patch-clamp technique, we applied riluzole on recombinant voltage-gated skeletal muscle sodium and adult nicotinic acetylcholine receptor channels expressed in a mammalian cell line (HEK 293). Riluzole blocked the inactivated state of voltage-gated skeletal muscle sodium channels, shifting the midpoint of the steady-state inactivation curve to more negative potentials, but only in comparatively high concentrations (> or = 0.1 mM). At these concentrations, riluzole also caused an open-channel block at acetylcholine receptor channels. We conclude that riluzole has only a mild blocking effect on the inactivated state of voltage-gated skeletal muscle sodium channels and nicotinic acetylcholine receptor channels. As the plasma concentration of riluzole in amyotrophic lateral sclerosis (ALS) patients approximates 2 microM, it seems unlikely that asthenia is caused by a block of skeletal muscle sodium channels or acetylcholine receptor channels by riluzole.

Dose-Response Relationship, Drug↗
PubMed2001

The anesthetic propofol modulates gating in paramyotonia congenita mutant muscle sodium channels.

We examined the effects of propofol on a paramyotonia congenita mutant skeletal muscle sodium channel in vitro, because life-threatening complications resulting from severe muscle rigidity during induction of anesthesia have been observed using other anesthetics in patients with hereditary sodium channel myopathies. Our hypothesis was that propofol might interact directly with mutant channels, causing enhanced muscle excitability in affected patients. Whole-cell voltage-clamp experiments were performed on HEK 293 cells expressing R1448H mutant sodium channels. Propofol blocked sodium inward current at clinical concentrations (5 micromol/L) when depolarizing pulses were started from holding potentials close to the physiological resting potential (-70 mV). Higher propofol concentrations (>/=25 micromol/L) accelerated pathologically delayed inactivation kinetics and delayed pathologically enhanced recovery from inactivation. Our in vitro results show that inactivation-deficient sodium channels are specifically targeted and blocked by propofol. This might reduce enhanced muscle excitability experienced by affected patients in vivo.

Amino Acid Substitution↗
PubMed2004

First chemical synthesis of a scorpion alpha-toxin affecting sodium channels: the Aah I toxin of Androctonus australis hector.

Aah I is a 63-residue alpha-toxin isolated from the venom of the Buthidae scorpion Androctonus australis hector, which is considered to be the most dangerous species. We report here the first chemical synthesis of Aah I by the solid-phase method, using a Fmoc strategy. The synthetic toxin I (sAah I) was renatured in DMSO-Tris buffer, purified and subjected to thorough analysis and comparison with the natural toxin. The sAah I showed physico-chemical (CD spectrum, molecular mass, HPLC elution), biochemical (amino-acid composition, sequence), immunochemical and pharmacological properties similar to those of the natural toxin. The synthetic toxin was recognized by a conformation-dependent monoclonal anti-Aah I antibody, with an IC50 value close to that for the natural toxin. Following intracerebroventricular injection, the synthetic and the natural toxins were similarly lethal to mice. In voltage-clamp experiments, Na(v) 1.2 sodium channel inactivation was inhibited by the application of sAah I or of the natural toxin in a similar way. This work describes a simple protocol for the chemical synthesis of a scorpion alpha-toxin, making it possible to produce structural analogues in time.

Animals↗
PubMed1997

Restoration of fast inactivation in an inactivation-defective human heart sodium channel by the cysteine modifying reagent benzyl-MTS: analysis of IFM-ICM mutation.

It has been suggested that the region linking domain III and IV of voltage-gated sodium channels forms the inactivation gate. A combination of site-directed mutagenesis, cysteine covalent modification, and electrophysiological recording techniques was used to identify the role of the Phe1486, a conserved phenylalanine residue located in the III-IV linker of Na+ channels. This Phe1486 is part of a hydrophobic amino acid cluster (IFM) that was proposed to play an essential role in the fast inactivation of voltage-gated sodium channels. Expression in tsA201 cells of an altered human heart 1 Na+ channel (hH1/F1486C) in which Phe1486 was replaced by a cysteine is associated with the appearance of a residual current, a loss of voltage-dependence of the time constants of inactivation, a shift of the steady-state inactivation to more depolarized voltages, and a recovery from inactivation that is faster than the wild-type hH1. Exposure of the cytoplasmic surface of mutant F1486C to the methanthiosulfonate reagents, MTSEA, MTSET, and MTSES, further disrupted macroscopic inactivation, but exposure to MTSBN completely restores fast inactivation and the voltage-dependence of fast inactivation. These findings support the formulation that the IFM motif of the III-IV-linker of voltage-gated sodium channels serves as an essential component of the inactivation particle and that the phenyl group of Phe1486 may play a crucial role in inactivation gate closure.

Cell Line↗
PubMed1996

Regulatory volume increase of human non-pigmented ciliary epithelial cells.

Cells (ODM/SV40) derived from human non-pigmented ciliary epithelial cells were studied by electronic cell sizing. After transiently suspending the cells in hypotonic solution, isotonicity was restored by addition of sucrose. The cell volumes (vc) initially fell below those of control isotonic suspensions, and subsequently increased towards the baseline level. This secondary increase in vc is termed the regulatory volume increase (RVI). Results obtained with ionic substitutions and transport inhibitors indicate that four ionic mechanisms can support the RVI in these cells: coupled Na+/H+ and Cl-/HCO3- antiports, a Na+/Cl- symport, a Na+/K+/2Cl- symport, and a Na+ channel in parallel with a Cl-/HCO3- antiport. Arachidonic acid metabolites regulate the RVI very differently from their effects on the regulatory volume response (RVD) of the same cells to cell swelling. Prostaglandin E2 (PGE2), leukotriene (LTD4) and the PKC-inhibitor staurosporine all inhibit the RVI. Blockade of the cyclooxygenase, lipoxygenase and epoxygenase pathways of arachidonic acid metabolism [with 5,8,11,14-eicosatetraynoic acid (ETYA)] produces a net acceleration of the RVI. In contrast, PGE2 and staurosporine stimulate, LTD4 has no effect, and ETYA inhibits the RVD. We suggest that knowledge of the ionic mechanisms and intracellular signalling underlying the RVI phenomenon may provide a basis for reducing the rate of net aqueous humor formation by increasing the rate of reabsorption of fluid from the aqueous humor into the non-pigmented ciliary epithelial cells.

Biological Transport, Active↗
PubMed2002

Inhibition of neuronal Na+ channels by the novel antiepileptic compound DCUKA: identification of the diphenylureido moiety as an inactivation modifier.

In a previous analysis of existing antiseizure compounds, we suggested that a common diphenylureido moiety was responsible for the activity-dependent, Na(+) channel blocking actions of these drugs (L. D. Snell et al., 2000, J. Pharmacol. Exp. Ther. 292: 215-227). Thus the novel diphenylureido compound [N,N-(diphenyl)-4-ureido-5,7-dichloro-2-carboxyquinoline] DCUKA was developed to incorporate the diphenylureido pharmacophore into a structure that also acted as an NMDA receptor antagonist. DCUKA has previously been shown to have antiepileptic properties in animals, and in the present study the actions of DCUKA on Na(+) currents were characterized using transfected cells that stably expressed the rat brain Na(v)1.2 channel isoform. In whole-cell voltage-clamp recordings, DCUKA reduced Na(+) currents in a dose- and membrane potential-dependent fashion, with an apparent 1:1 stoichiometry of drug:channel interaction. Characterization of the effects of DCUKA on Na(+) channel function strongly suggested that DCUKA acts by enhancing Na(+) channel inactivation. Thus in the presence of DCUKA, Na(v)1.2 channels showed reduced availability in steady-state inactivation protocols, displayed use-dependent inhibition, and were slower to recover from inactivation than untreated channels, while DCUKA showed no significant interaction with the open state of the channel. As previously postulated for the anticonvulsants carbamazepine and phenytoin, these results could be well explained by a model in which the drug preferentially interacts with the fast inactivated state of the channel. Finally, DCUKA was generally more efficacious than carbamazepine in modifying sodium channel behavior. Thus the diphenylureido moiety identified by a structural analysis of classic anticonvulsants appears to be important to the inactivation-specific Na(+) channel inhibition by this class of antiseizure agents.

Animals↗
PubMed1996

Rotational fluctuation of the sodium-driven flagellar motor of Vibrio alginolyticus induced by binding of inhibitors.

Rotation of the Na(+)-driven flagellar motor of Vibrio alginolyticus was investigated under the influence of inhibitors specific to the motor, amiloride and phenamil. The rotation rate of a single flagellum on a cell stuck to a glass slide was examined using laser dark-field microscopy. In the presence of 50 mM NaCl, the average rotation rate (omega) was about 600 r.p.s. with a standard deviation (sigma omega) of 9% of omega. When omega was decreased to about 200 r.p.s. by the presence of 1.5 mM amiloride, sigma omega increased to 15% of omega. On the other hand, when omega was decreased to about 200 r.p.s. by the addition of 0.6 microM phenamil, a large increase in sigma omega up to 50% of omega, was observed. Similarly large fluctuations were observed at other concentrations of phenamil. These observations suggest that dissociation of phenamil from the motor was much slower than that of amiloride. A very low concentration of phenamil caused a transient but substantial reduction in rotation rate. This might suggest that binding of only a single molecule of phenamil strongly inhibits the torque generation in the flagellar motor.

Amiloride↗
PubMed1999

Structural and electrophysiological effects of local anesthetics and of low temperature on myelinated nerves: implication of the lipid chains in nerve excitability.

X-ray scattering and electrophysiological experiments performed on toad sciatic nerves as a function of the exposure to either low temperature or tetracaine yielded the following results: (i) the main structural effect is to thicken the individual membranes, thus to stiffen the acyl chains and increase the repeat distance of the one-dimensional lattice, phenomena that are typical of lipid-containing systems with disordered chains; (ii) the electrophysiological effect is to decrease the amplitude and velocity of the compound action potential; (iii) the structural and physiological effects of the two agents are practically identical. Since the structural and the electrophysiological parameters have different origins in the nerves (the structure regards the myelin sheath, the electrical signals originate at the nodes of Ranvier) it is inferred that tetracaine and low temperature exert similar effects on the membranes of both the myelin sheath and the nodes of Ranvier. Also, since local anesthetics act by inhibiting the Na+ channels, these observations suggest that the acyl chain conformation modulates the channel function and thus the generation of action potential.

Action Potentials↗
PubMed1994

Age-related quinidine effects on ionic currents of rabbit cardiac myocytes.

Age-related cardiac actions of quinidine have been shown in prolongation of action potential duration, but not in the tonic and use-dependent block of the maximal velocity of action potential upstroke. To elucidate the underlying ionic mechanisms, currents through the Na, Ca and K channels were examined by using a whole-cell voltage clamp technique on isolated neonatal (< 5 day) and adult (> 3 months) rabbit cardiac myocytes under various concentrations (0.5, 1.5 and 4.5 microM) of quinidine. In neonatal and adult myocytes, quinidine caused a comparable degree of dose-dependent effects on Na currents including decrease in peak Na currents, left-shift of steady-state availability curve and slowing of the recovery from inactivation. However, the inwardly rectifier K current and the transient outward current were suppressed to a greater extent in the neonatal myocytes than in the adult (P = 0.0002 and 0.02, respectively). On the contrary, the magnitude of decrease in peak Ca currents after quinidine treatment was much smaller in the neonatal myocytes than in the adult (P = 0.01). These findings indicate that age-related ionic channel-block by quinidine is complex; and shows major differences in the Ca and K currents of cardiac myocytes. Accordingly, a differential therapeutic potential of quinidine may exist in hearts of different ages.

Action Potentials↗
PubMed2000

Functional suppression of sodium channels by beta(1)-subunits as a molecular mechanism of idiopathic ventricular fibrillation.

Ventricular fibrillation leading to sudden cardiac death can occur even in the absence of structural heart disease. One form of this so-called idiopathic ventricular fibrillation (IVF) is characterized by ST segment elevation (STE) in the electrocardiogram. Recently we found that IVF with STE is linked to mutations of SCN5A, the gene encoding the cardiac sodium channel alpha -subunit. Two types of defects were identified: loss-of-function mutations that severely truncate channel proteins and missense mutations (e.g. a double mutation, R1232W and T1620M) that cause only minor changes in channel gating. Here we show that co-expression of the R1232W+T1620M missense mutant alpha -subunits in a mammalian cell line stably transfected with human sodium channel beta(1)-subunits results in a phenotype similar to that of the truncation mutants. In the presence of beta(1)subunits the expression of both ionic currents and alpha -subunit-specific, immunoreactive protein was markedly suppressed after transfection of mutant, but not wild-type alpha -subunits when cells were incubated at physiological temperature. Expression was partially restored by incubation at reduced temperatures. Our results reconcile two classes of IVF mutations and support the notion that a reduction in the amplitude of voltage-gated sodium conductance is the primary cause of IVF.

Animals↗
PubMed2001

Late sodium current is a novel target for amiodarone: studies in failing human myocardium.

V. A. Maltsev, H. N. Sabbah and A. I. Undrovinas. Late Sodium Current is a Novel Target for Amiodarone: Studies in Failing Human Myocardium. Journal of Molecular and Cellular Cardiology (2001) 33, 923-932. The authors recently reported the existence of a novel late Na(+)current (I(NaL)) in ventricular cardiomyocytes (VC) isolated from both normal and failing human hearts. Both in failing human and canine VC, partial block of I(NaL)normalized action potential (AP) duration and abolished early after depolarizations (EADs). The most recent computer simulation studies indicate a significant contribution of the persistent Na(+)current into the ion current balance on the plateau of VC AP as well as its important role in the dispersion of AP duration across the ventricular wall. The data thus indicate a possibility for I(NaL)to be a new therapeutic target. The present study tested a hypothesis that I(naL)could be a novel target for amiodarone (AMIO). Midmyocardial VC isolated from left ventricle of explanted failing human hearts were measured by a whole-cell clamp. I(NaL)was effectively blocked by AMIO in therapeutic concentrations, with IC(50)being 6.7+/-1.1 microM (mean+/-S.E.M., n=16 cells). At the same time, AMIO (5 microM ) produced almost no effect on the transient Na(+)current (IC(50)=87+/-28 microM, n=8). AMIO significantly shifted the steady-state inactivation (SSI) curve of I(NaL)towards more negative potentials and accelerated decay time course in a dose-dependent manner. At 5 microM, AMIO shifted SSI by 21+/-3 mV (n=7) and decreased the decay time constant from 0.67+/-0.05 s to 0.37+/-0.04 s (n=5, P<0.004). Evaluation of AMIO binding to different Na(+)channel (NaCh) states by means of mathematical models describing dose-dependent SSI shift and decay acceleration was consistent with an action that AMIO blocks NaCh preferentially in inactivated and activated states rather than in resting state. The authors conclude that the late Na(+)current is effectively blocked by AMIO and represents a new target for the drug in patients with chronic heart failure (HF).

Amiodarone↗
PubMed2006

Mutation-specific pharmacology of the long QT syndrome.

The congenital long QT syndrome is a rare disease in which inherited mutations of genes coding for ion channel subunits, or channel interacting proteins, delay repolarization of the human ventricle and predispose mutation carriers to the risk of serious or fatal arrhythmias. Though a rare disorder, the long QT syndrome has provided invaluable insight from studies that have bridged clinical and pre-clinical (basic science) medicine. In this brief review, we summarize some of the key clinical and genetic characteristics of this disease and highlight novel findings about ion channel structure, function, and the causal relationship between channel dysfunction and human disease, that have come from investigations of this disorder.

Action Potentials↗