Permeability Of Sodium Channels Research Articles

Terahertz Waves Enhance the Permeability of Sodium Channels

With the help of molecular dynamics simulations and an artificial sodium channel model, we corroborated that the application of terahertz stimulation at a characteristic frequency can largely increase the permeability of the sodium channel by a factor of 33.6. The mechanism is that the carboxylate groups in the filter region transfer the absorbed terahertz photon energy to the sodium ions, which increase the ions’ kinetic energy; this results in breaking the hydrated hydrogen bonding network between the hydrosphere layer of the ions and the carboxylate groups, thereby increasing their diffusion and reducing the energy barrier for them to cross the channel. This study on terahertz-driven particle transmembrane transport offers new ideas for targeted therapy of channel diseases and for developing novel integrated engineering systems in energy conversion and storage.

Impact of the metabolic syndrome on peripheral nerve structure and function in type 2 diabetes.

There is a strong association between the metabolic syndrome in diabetes and the development of peripheral neuropathy; however, the pathophysiological mechanisms remain unknown. Participants with type 2 diabetes and metabolic syndrome (T2DM/MetS, n=89) and type 2 diabetes alone (T2DM; n=59) underwent median nerve ultrasound and excitability studies to assess peripheral nerve structure and function. A subset of T2DM/MetS (n=24) and T2DM (n=22) participants underwent confocal microscopy to assess central and inferior whorl corneal nerve structure. Neuropathy severity was assessed using the modified Toronto Clinical Neuropathy Score (mTCNS). Diabetes groups were similar for age, sex distribution, diabetes duration, hemoglobin A1c , insulin treatment, and renal function. Sixty healthy controls similar for age and sex distribution were recruited for comparison. Participants with T2DM/MetS manifested with a greater mTCNS compared to T2DM (p<0.05). Median nerve cross-sectional area was larger in the T2DM/MetS group compared to the T2DM cohort (p<0.05). Participants with T2DM/MetS had reductions in central (all p<0.01) and inferior whorl (all p<0.05) nerve measures. Compared to T2DM, the T2DM/MetS group demonstrated more severe changes in nerve excitability measures, which was due to reduced sodium channel permeability and sodium-potassium pump function. In comparison, only sodium channel permeability was reduced in the T2DM group. Compared to participants with type 2 diabetes alone, those with diabetes and metabolic syndrome manifested greater alterations in peripheral nerve structure and function, which may be due to reduced function of the sodium-potassium pump.

A Tool for Computation of Changes in Na+, K+, Cl- Channels and Transporters Due to Apoptosis by Data on Cell Ion and Water Content Alteration.

Monovalent ions are involved in a vast array of cellular processes. Their movement across the cell membrane is regulated by numerous channels and transporters. Identification of the pathways responsible for redistribution of ions and cell water in living cells is hampered by their strong interdependence. This difficulty can be overcome by computational analysis of the whole cell flux balance. Our previous computational studies were concerned with monovalent ion fluxes in cells under the conditions of balanced ion distribution or during transition processes after stopping the Na+/K+ pump. Here we analyze a more complex case—redistribution of ions during cell apoptosis when the parameters keep changing during the process. New experimental data for staurosporine-induced apoptosis of human lymphoma cells U937 have been obtained: the time course of changes in cellular K+, Na+, Cl−, and water content, as well as Rb+ fluxes as a marker of the Na/K pump activity. Using a newly developed computational tool, we found that alteration of ion and water balance was associated with a 55% decrease in the Na+/K+-ATPase rate coefficient over a 4-h period, with a time-dependent increase in potassium channel permeability, and a decrease in sodium channel permeability. The early decrease in [Cl−]i and cell volume were associated with an ~5-fold increase in chloride channel permeability. The developed approach and the presented executable file can be used to identify the channels and transporters responsible for alterations of cell ion and water balance not only during apoptosis but in other physiological scenarios.

Lidocaine-induced potentiation of thermal damage in skin and carcinoma cells.

Lidocaine acts as a local anesthetic by blocking transmembrane sodium channel permeability, but also induces the synthesis of heat shock proteins and sensitizes cells to hyperthermia. A previous study reported two cases of deep focal skin ulceration at points corresponding to depot local lidocaine injection sites after treatment with non-ablative fractional resurfacing and it was hypothesized that lidocaine had focally sensitized keratinocytes to the thermal damage of laser treatment. The objective of this study was to investigate whether lidocaine potentiates hyperthermia damage to both normal and cancerous skin cells using an in vitro model. Normal skin cell lines (fibroblasts, keratinocytes), skin cancer cell lines (melanoma, basal cell carcinoma), and a mucosal cancer cell line (cervical carcinoma) were exposed to various concentrations of lidocaine (0-0.3%) with or without hyperthermia (37°C, 42°C). Compared to normal skin cells, we demonstrate that cancer cell lines show significantly increased cell toxicity when a moderate temperature (42°C) and low lidocaine concentrations (0.1-0.2%) are combined. The toxicity directly correlates with a higher percentage of cells in S-phase (28-57%) in the cancer cell lines compared to normal skin cell lines (13-19%; R-square 0.6752). These results suggest that lidocaine potentiates thermal sensitivity of cell cycle active skin cells. The direct correlation between cell toxicity and S-phase cells could be harnessed to selectively treat skin and mucosal cancer cells while sparing the surrounding normal tissue. Additional research pre-clinically and clinically using several different heat sources (e.g., lasers, ultrasound, etc.) and lidocaine concentrations is needed to confirm and optimize these results. Lidocaine-enhanced hyperthermia may provide a non-invasive, alterative treatment option for highly proliferating, superficial skin, and mucosal lesions such as cancer or warts. Lasers Surg. Med. 51:88-94, 2019. © 2018 Wiley Periodicals, Inc.

The role of the lateral habenula in punishment.

The lateral habenula (LHb) is a small epithalamic structure that projects via the fasciculus retroflexus to the midbrain. The LHb is known to modulate midbrain dopamine (DA) neurons, including inhibition of ventral tegmental area (VTA) neurons via glutamatergic excitation of the GABAergic rostromedial tegmental nucleus (RMTg). A variety of lines of evidence show activity in LHb and the LHb-RMTg pathway is correlated with, and is sufficient to support, punishment learning. However, it is not immediately clear whether LHb is necessary for punishment. Here we used a within-subjects punishment task to assess the role of LHb in the acquisition and expression of punishment as well as in aversive choice. Rats that pressed two individually presented levers for pellet rewards rapidly suppressed responding to one lever if it also caused footshock deliveries (punished lever) but continued pressing a second lever that did not cause footshock (unpunished lever). Infusions of an AMPA receptor antagonist (NBQX) into LHb had no effect on the acquisition or expression of this punishment, or on aversive choice, but did increase locomotion. Infusion of the sodium channel blocker bupivacaine likewise had no effect on expression of punishment. However, infusion of the calcium channel blocker mibefradil did affect expression of punishment by significantly decreasing the latency with which rats responded on the punished lever and significantly increasing unpunished lever-pressing. Taken together, these findings indicate that the LHb plays a limited role in punishment, influencing only latency to respond. This role is linked to calcium channel permeability and not AMPA receptor or sodium channel permeability.

Epigenetics and Hypertension

Epigenetics refers to mechanisms for environment-gene interactions (mainly by methylation of DNA and modification of histones) that do not alter the underlying base sequence of the gene. This article reviews evidence for epigenetic contributions to hypertension. For example, DNA methylation at CpG islands and histone acetylation pathways are known to limit nephron development, thereby unmasking hypertension associated with exposure to a high-salt diet. Maternal water deprivation and protein deficiency are shown to increase expression of renin-angiotensin system genes in the offspring. The methylation pattern of a serine protease inhibitor gene in human placentas is shown to be a marker for preeclampsia-associated hypertension. Mental stress induces phenylethanolamine n-methyltransferase, which may act as a DNA methylase and mimic the gene-silencing effects of methyl CpG binding protein-2 on the norepinephrine transporter gene, which, in turn, may exaggerate autonomic responsiveness. A disrupter of telomeric silencing (Dot1) is known to modulate the expression of a connective-tissue growth-factor gene associated with blood vessel remodeling, which could alter vascular compliance and elastance. Dot1a also interacts with the Af9 gene to produce high sodium channel permeability and silences the hydroxysteroid dehydrogenase-11β2 gene, thereby preventing metabolism of cortisol to cortisone and overstimulating aldosterone receptors. These findings indicate targets for environment-gene interactions in various hypertensive states and in essential hypertension.

Cardiac effects of “mad honey”: a case series

Background. Grayanotoxins (GTX), also known as andromedotoxins, are produced by plants of the Ericacae family. This toxin is responsible for “mad honey” intoxication, which can present with fatal cardiac bradyarrhythmias and circulatory collapse. GTXs lead to cardiac toxicity because they increase sodium channel permeability and activate the vagus nerve. Objective. We evaluated 42 patients (33 males) prospectively who had been hospitalized with diagnosis of “mad honey” intoxication in a state hospital setting. Methods and results. The median age of patients was 48.5 years and all patients were admitted with complaints of nausea, vomiting, dizziness, fainting, and sweating. Five of the patients had syncope before admission. On admission, the mean systolic blood pressure was 73.1 ± 12.7 mmHg, the mean diastolic blood pressure was 52.1 ± 11.3mmHg, mean heart rate was 38 ± 7 bpm. On initial electrocardiograms, 18 patients had sinus bradycardia, 15 patients had complete atrioventricular block, and 9 patients had nodal rhythm. All patients were monitored in a coronary care unit and treated sympomatically with atropine, intravenous fluids, and dopamine. None of the patients needed temporary pacing and all were discharged without complications. Conclusion. “Mad honey,” which is produced widely in northern parts of Turkey can be toxic. This intoxication should be considered in patients admitted to emergency department with bradycardia and hypotension especially in regions where this honey is produced.

Pharmacologically Induced/Exacerbated Restless Legs Syndrome, Periodic Limb Movements of Sleep, and REM Behavior Disorder/REM Sleep Without Atonia: Literature Review, Qualitative Scoring, and Comparative Analysis

Pharmacologically induced/exacerbated restless legs syndrome (RLS), periodic limb movements in sleep (PLMS), and REM behavior disorder/REM sleep without atonia (RSWA) are increasingly recognized in clinical sleep medicine. A scoring system to evaluate the literature was created and implemented. The aim was to identify the evidence with the least amount of confound, allowing for more reliable determinations of iatrogenic etiology. Points were provided for the following criteria: manuscript type (abstract, peer-reviewed paper); population size studied (large retrospective study, small case series, case report); explicitly stated dosage timing; identification of peak symptoms related to time of medication administration (i.e., medication was ingested in the evening or at bedtime); initiation of a treatment plan; symptoms subsided or ceased with decreased dosage or drug discontinuation (for RLS articles only); negative personal history for RLS prior to use of the medication; exclusion of tobacco/alcohol/excessive caffeine use; exclusion of sleep disordered breathing by polysomnography (PSG); and PSG documentation of presence or absence of PLMS. For RLS and PLMS articles were also given points for the following criteria: each 2003 National Institutes of Health (NIH) RLS criteria met; exclusion of low serum ferritin; and exclusion of peripheral neuropathy by neurological examination. Thirty-two articles on drug-induced RLS, 6 articles on drug-induced PLMS, and 15 articles on drug-induced RBD/ RSWA were analyzed. Based on scores < or = 10 and trials of medication reduction/cessation, the strongest evidence available for drug induced RLS are for the following drugs: escitalopram; fluoxetine; L-dopa/carbidopa and pergolide; L-thyroxine; mianserin; mirtazapine; olanzapine; and tramadol. Since none of the PLMS articles assessed PLMI in trials of medication reduction/cessation, the strongest evidence based on scores > or = 10 are for the following drugs: bupropion, citalopram, fluoxetine, paroxetine, sertraline, and venlafaxine. Based on scores > or = 10 and/or trials of medication cessation, the strongest evidence for drug induced RBD/ RSWA is for the following drugs: clomipramine, selegiline, and phenelzine.

Ethanol modulates the ionic permeability of sodium channels in rat sensory neurons.

The effects of ethanol on tetrodotoxin-sensitive (TTXs) and tetrodotoxin-resistant (TTXr) sodium channels in rat spinal ganglia were studied using a patch-clamp method. Application of ethanol (10 and 100 mM) to both sides of membranes resulted in decreases in the reversion potentials of both types of sodium channels. In the case of TTXr channels, ethanol decreased their selectivity in relation to Na ions and altered the sequence of ion selectivity of these channels for different cations from row X to row XI of the Eisenman selectivity classification. It is suggested that this change in ion selectivity is associated with ethanol-induced disruption of hydrogen bonds which stabilize the spatial structure of ion channel macromolecules, which may lead to changes in the steric parameters of the pores formed by these channels.

Toxin 2 (PhTx2), a neurotoxic fraction from Phoneutria nigriventer spider venom, causes acute morphological changes in mouse skeletal muscle

Phoneutria nigriventer (Labidognatha, Ctenidae) is a spider found in the warm regions of South America. Bites by this species cause intense local pain, autonomic dysfunction and paralysis. PhTx2, a neurotoxic fraction of the venom of this species, interferes with the physiology of sodium channel function. The present study describes the morphological changes in mouse phrenic nerve and diaphragm muscle after 15, 30, 45 and 60 min of incubation with 1 μg of PhTx2/ml. Light and transmission electron microscopy showed that PhTx2 caused progressive myonecrosis which involved swelling of the sarcoplasmic reticulum, mitochondrial damage, disorganization of the sarcomeres, zones of hypercontracted myofibrils and rupture of the plasma membrane. The intramuscular fascicles of the phrenic nerve showed vacuolated myelinated axons and Schwann cells. The neuromuscular junctions had vesicle-depleted nerve terminals with swollen mitochondria. The axolemma was frequently invaginated and sequestered portions of the axoplasm, or was sometimes interrupted at the site of the synaptic gutter. The post-synaptic junctional folds were shallow and disperse. These morphological alterations in the muscle and nerve fibres were similar to those caused by osmotic disturbances and agree with the ability of PhTx2 to increase the permeability of sodium channels. An increase in sodium influx would probably be accompanied by an influx of water and an elevation in the concentration of cytosolic calcium as a result of calcium release by the sarcoplasmic reticulum and/or mitochondria and the entry of extracellular calcium. The morphological effects caused by PhTx2 were comparable to those seen with Phoneutria nigriventer whole venom which is known to activate and to delay the inactivation of sodium channels. We conclude that PhTx2 is probably the main toxic fraction responsible for such morphological alterations.

Dynamic selectivity filters in ion channels.

This work was supported by a Wellcome Trust (UK) International Prize Travelling Fellowship and the NIH (NS-11756).

Conduction along myelinated and demyelinated nerve fibres with a reorganized axonal membrane during the recovery cycle: model investigations

The changes in the excitability of the reorganized axonal membrane in myelinated and demyelinated nerve fibres as well as the causes conditioning such changes have been investigated by paired stimulation during the first 30 ms of the recovery cycle. The variations of the action potential parameters (amplitude and velocity) are traced also. The simulation of the conduction along the normal fiber is based on the Frankenhaeuser and Huxley (1964) and Goldman and Albus (1968) equations, while the demyelination is considered to be an elongation of the nodes of Ranvier. The axonal membrane reorganization is achieved by means of potassium channel blocking and increase of the sodium-channel permeability. It is shown that potassium channels block decreases membrane excitability for the myelinated and demyelinated fibres in the cases of initial and paired stimulation. With increasing sodium-channel permeability on the background of the blocked potassium channels, the membrane excitability is increased. For the fibres with a reorganized membrane, a supernormality of the membrane excitability is obtained, the latter remaining unrecovered during the 30 ms cycle under investigation. The supernormality of the excitability grows from the demyelinated fibre without reorganized membrane to the demyelinated fibre with reorganized one. For short interstimulus intervals, the second action potential propagates along the fibres with a reduced velocity and a decreased amplitude. No supernormality of the potential parameters (amplitude, velocity) is observed during the cycle up to 30 ms.(ABSTRACT TRUNCATED AT 250 WORDS)

Model investigations of the temperature dependence of demyelinated and reorganized axonal membrane.

The temperature dependence (from 10 degrees to 50 degrees C) of the intracellular action potentials' parameters in a fiber with a simulated reorganization of the axonal membrane against the background of a systematic paranodal demyelination of the fiber was investigated. The temporal and spatial distribution of the potential as well as the ionic currents' kinetics have been represented. The reorganization of the axonal membrane was achieved by means of potassium channels blocking and increase of the sodium-channel permeability, while the demyelination was achieved by means of elongation of the nodes of Ranvier. In order to account for the temperature dependence of the rate constants and of the maximal sodium and potassium permeabilities, the temperature coefficients (Q10) have been used. It has been shown for the demyelinated and reorganized membrane that increased temperature blocks the conduction at temperatures much higher than the blocking temperature for the demyelinated fiber only. When temperature increases the amplitude of the potential decreases while the velocity increases up to temperatures approaching the blocking temperature after which it abruptly drops. The dependence of the asymmetry and the wavelength of the potential on temperature is complex and nonmonotonic. For the reorganized membrane at the background of a given degree of demyelination with increasing temperature the ionic currents' flow and the membrane conduction respectively increase, but, at lower temperatures, when the temperature increase is combined with the increased degree of the fiber demyelination, the conduction is blocked.

Intrasomatic and intradendritic recordings of plateau potentials in slices of the dentate gyrus maintained in vitro.

Intrasomatic and intradendritic recordings were performed in slices of the dentate gyrus maintained in vitro. When barium ions (2.4 mM) were substituted for calcium ions in the perfusing medium, plateau potentials appeared with an amplitude of 20-40 mV which lasted from 40 ms to more than one min; during these plateau potentials, the input membrane resistance was decreased. In the soma, plateau potentials were also observed in a medium containing barium ions + tetrodotoxin (0.3 or 0.6 microM); whereas, in the dendrites, the barium-induced plateau potentials were abolished after addition of tetrodotoxin to the barium containing perfusion. The somatic plateau potentials had a duration which appeared to be dependent on the stimulus frequency. After being in contact with the barium-tetrodotoxin solution for a long period, the soma membrane potential was observed to jump between two relatively stable levels: a resting state and a depolarized state. In conclusion, calcium conductances appear to be present both at the soma and the dendrites of dentate granule cells; however, at the dendritic level, it appears that, when sodium channel permeability is blocked by tetrodotoxin, there is insufficient inward current to support the generation of action potentials.

The permeability of sodium channels to hydrogen ions in nerve fibres.

Ionic currents in the node of Ranvier bathed in Na-free acid solutions (pH 3.4-4.6) were measured under voltage clamp conditions. Small (less than 0.1 nA) inward currents were detected in Na-free solutions at pH less than 4.0, whereas only outward currents were observed in Na-free solutions at normal pH. These currents have kinetics and voltage dependence of activation similar to those of sodium currents at low pH. They were blocked by tetrodotoxin (TTX) and benzocaine. After pretreatment of the membrane with aconitine both inward and outward ionic currents in Na-free acid solutions acquired a kinetics and voltage dependence of activation similar to those of the currents in aconitine-modified sodium channels at low pH. TTX and benzocaine inhibited these currents. Inward currents in aconitine-treated membrane appeared at pH 4.6 and were about ten times as large as those in untreated membrane. Both inward and outward ionic currents in Na-free acid solutions were suggested to be through normal or aconitine-modified sodium channels. Experiments with various concentrations of substituting cations [tris(hydroxymethyl)aminomethane, tetraethylammonium, choline], Ca2+ and H+ in Na-free acid solutions showed that the inward currents in normal and aconitine-modified sodium channels were carried by hydrogen ions. Hydrogen to sodium permeability ratio was determined from reversal potential measurements. It equals to (mean +/- S.E.) 252 +/- 16 and 1182 +/- 74 for normal and aconitine-modified sodium channels, respectively. The data obtained can be explained on assumption that in sodium channel energetic barriers for H+ are much lower than those for Na+. H+, however, passes through the channel very slowly because of the low rate of its removal from the acid group in selectivity filter.

Chemical modification reduces the conductance of sodium channels in nerve.

Tetrodotoxin (TTX) and saxitoxin (STX) are extremely potent poisons that prevent nerve and muscle cells from producing action potentials by blocking sodium channels. If the channels are modified by reagents that act on carboxyl groups, however, both the binding of these toxins and their effect on the action potential are reduced. One such reagent, trimethyloxonium ion (TMO) converts channels into a form that is not blocked by TTX concentrations 10(5) times greater than its normal Kd (ref. 6). Most such chemical modifications of sodium channels also reduce the measured membrane sodium current, but it has not been known whether such reductions were due to a change in the number of channels, in permeability properties, or in gating properties. We now report that TMO-modified, TTX-resistant sodium channels have a smaller single-channel conductance (gamma) with a more linear instantaneous current-voltage relationship than that of normal channels, and that the measured reduction in gamma accounts for all of the decrease in sodium current after TMO treatment. This change in sodium channel permeability properties can be explained by the removal of a fixed negative charge near the outside of the channel.

Permeability of the sodium channel in Myxicola to organic cations.

The relative permeability of sodium channels to organic cations was determined in the Myxicola giant axon. Ionic currents under potential control were measured in seawater and in sodium-free solutions containing the organic cation. The measured reversal potential and the Goldman equation were used to obtain the relative permeabilities. The permeability sequence was found to be: sodium greater than hydroxylamine greater than hydrazine greater than ammonium greater than guanidine greater than formamidine greater than aminoguanidine greater than methylamine. Measurements were also made on sodium and several of the organic cations at different concentrations. The relative permeabilities of the ions were found to be independent of concentration. Qualitatively, the permeability sequence for the Myxicola giant axon was similar to that of the frog node of Ranvier.

The permeability of the sodium channel to metal cations in myelinated nerve.

The relative permeability of sodium channels to eight metal cations is studied in myelinated nerve fibers. Ionic currents under voltage-clamp conditions are measured in Na-free solutions containing the test ion. Measured reversal potentials and the Goldman equation are used to calculate the permeability sequence: Na(+) approximately Li(+) > Tl(+) > K(+). The ratio P(K)/P(Na) is 1/12. The permeabilities to Rb(+), Cs(+), Ca(++), and Mg(++) are too small to measure. The permeability ratios agree with observations on the squid giant axon and show that the reversal potential E(Na) differs significantly from the Nernst potential for Na(+) in normal axons. Opening and closing rates for sodium channels are relatively insensitive to the ionic composition of the bathing medium, implying that gating is a structural property of the channel rather than a result of the movement or accumulation of particular ions around the channel. A previously proposed pore model of the channel accommodates the permeant metal cations in a partly hydrated form. The observed sequence of permeabilities follows the order expected for binding to a high field strength anion in Eisenman's theory of ion exchange equilibria.

The permeability of the sodium channel to organic cations in myelinated nerve.

The relative permeability of sodium channels to 21 organic cations was studied in myelinated nerve fibers. Ionic currents under voltage-clamp conditions were measured in sodium-free solutions containing the test cation. The measured reversal potential and the Goldman equation were used to calculate relative permeabilities. The permeability sequence was: sodium approximately hydroxylamine > hydrazine > ammonium approximately formamidine approximately guanidine approximately hydroxyguanidine > aminoguanididine >> methylamine. The cations of the following compounds were not measurably permeant: N-methylhydroxylamine, methylhydrazine, methylamine, methylguanidine, acetamidine, dimethylamine, tetramethylammonium, tetraethylammonium, ethanolamine, choline, tris(hydroxymethyl)amino methane, imidazole, biguanide, and triaminoguanidine. Thus methyl and methylene groups render cations impermeant. The results can be explained on geometrical grounds by assuming that the sodium channel is an oxygen-lined pore about 3 A by 5 A in cross-section. One pair of oxygens is assumed to be an ionized carboxylic acid. Methyl and amino groups are wider than the 3 A width of the channel. Nevertheless, cations containing amino groups can slide through the channel by making hydrogen bonds to the oxygens. However, methyl groups, being unable to form hydrogen bonds, are too wide to pass through.