Skeletal Muscle Sodium Channel Research Articles

Tryptophan Scanning Mutagenesis to Identify the Residues Involved in Coupling between the Pore and DIII Voltage-Sensor of a Sodium Channel

In response to membrane depolarization, voltage-gated ion channels undergo a structural rearrangement that moves the voltage sensing segments in the electric field and initiates a series of conformational transitions that ultimately opens the channel pore. The mechanism of coupling between the voltage-sensing domain and pore domain remains poorly understood. To characterize the molecular basis of this coupling, we have systematically substituted tryptophan residues in the S4-S5 region (from C-terminus of S4 to N-terminus of S5) and C-terminus of S6 of domain III in the skeletal muscle sodium channel. The effects of these perturbations on the movement of the voltage-sensor were monitored by using a site-specific fluorescent reporter on S4 of domain III using voltage-clamp fluorometry. Conformational changes in the pore were tracked by measuring the inward sodium currents. Our study identifies a number of mutants, which stabilize the voltage-sensors in the activated conformation while destabilizing the open pore conformation relative to the wild type. We suggest that the residues at these positions play an important role in coupling the voltage-sensor of domain III to the pore of the sodium channel. Support: National Institutes of Health, American heart Association and Shaw Scientist Award.

Charge Immobilization From The Open And Closed States Of Voltage-Gated Sodium Channels

We compared the immobilization of voltage sensor gating charge during open- and closed-state fast inactivation in skeletal muscle sodium channels. To do this we compared charge movement and its immobilization using ionic and gating current recordings in the cut open oocyte configuration. Charge movement and its immobilization were steeply voltage dependent at subthreshold voltages. Kinetics of charge immobilization during open- or closed-state fast inactivation were more rapid than the concomitant decay of ionic current. The extent of charge immobilized was correlated with the completion of closed-state fast inactivation at the most negative pulse commands, and reached a maximum of 2/3 of the ON gating charge. Anthopleurin-A decreased the votlage dependence of charge immobilization compared to wild type channels. Whereas anthopleurin slowed open-state fast inactivation, the toxin accelerated currrent decrement at voltages for which only closed-state fast inactivation was possible. Anthopleurin selectively accelerated remobilzation of the gating charge in fast inactivated channels without slowing the onset or decreasing the extent of charge immobilized. This work was supported by NIH P20RR016454 to ISU.

Mutations in skeletal muscle

Mutations in skeletal muscle sodium channels (NaV1.4) cause periodic paralysis. Paramyotonia congenita and hyperkalemic periodic paralysis are caused by gain-of-function mutations spread widely through the protein, which increase channel activity and lead to repetitive firing or depolarization block. In contrast, mutations that cause hypokalemic (HypoPP) and normokalemic (NormoPP) periodic paralysis are localized in the outermost three gating-charge-carrying arginine residues (R1-R3) in the S4 segment in domain II, and they do not have major effects on sodium channel function as typically measured. Site-directed mutations of these residues cause gating pore current, a voltage-gated leak current through the voltage sensor (Sokolov et al., 2005); mutations of R1 and R2 cause gating pore current in the resting state, whereas mutation of R3 causes gating pore current in the activated state. Similar studies of the HypoPP mutant R2G revealed gating pore current of approximately 1% of peak current at the resting membrane potential, which was decreased by depolarization (Sokolov et al., 2007). This gating pore current was selective for Cs>K>Na and blocked by mM concentrations of divalent cations, Zn>Ba>Ca. A gating pore current of similar size was observed in the resting state for the HypoPP mutants R1H and R2H, but this current is selective for protons. In contrast to HypoPP, the mutations that cause NormoPP are in R3 (R3G/Q/W). All of these mutations cause gating pore conductance for sodium in the activated and slow-inactivated states, in which the voltage sensors are in their outward position. The common pathogenic feature of these mutations is likely to be depolarization and sodium overload, which are observed in patient biopsies. Dominant gain-of-function pathogenic effects may arise directly from excess sodium entry for R2G and R3G/Q/W and indirectly from excessive Na-H exchange for R1H and R2H.

Clinical Summaries

Clinical Summaries

Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy

Background and PurposeMutations of the skeletal muscle sodium channel gene SCN4A, which is located on chromosome 17q23-25, are associated with various neuromuscular disorders that are labeled collectively as skeletal muscle sodium channelopathy. These disorders include hyperkalemic periodic paralysis (HYPP), hypokalemic periodic paralysis, paramyotonia congenita (PMC), potassium-aggravated myotonia, and congenital myasthenic syndrome. This study analyzed the clinical and mutational spectra of skeletal muscle sodium channelopathy in Korean subjects.MethodsSix unrelated Korean patients with periodic paralysis or nondystrophic myotonia associated with SCN4A mutations were included in the study. For the mutational analysis of SCN4A, we performed a full sequence analysis of the gene using the patients' DNA. We also analyzed the patients' clinical history, physical findings, laboratory tests, and responses to treatment.ResultsWe identified four different mutations (one of which was novel) in all of the patients examined. The novel heterozygous missense mutation, p.R225W, was found in one patient with mild nonpainful myotonia. Our patients exhibited various clinical phenotypes: pure myotonia in four, and PMC in one, and HYPP in one. The four patients with pure myotonia were initially diagnosed as having myotonia congenita (MC), but a previous analysis revealed no CLCN1 mutation.ConclusionsClinical differentiating between sodium-channel myotonia (SCM) and MC is not easy, and it is suggested that a mutational analysis of both SCN4A and CLCN1 is essential for the differential diagnosis of SCM and MC.

Epicardial Border Zone Overexpression of Skeletal Muscle Sodium Channel SkM1 Normalizes Activation, Preserves Conduction, and Suppresses Ventricular Arrhythmia

In depolarized myocardial infarct epicardial border zones, the cardiac sodium channel (SCN5A) is largely inactivated, contributing to low action potential upstroke velocity (V(max)), slow conduction, and reentry. We hypothesized that a fast inward current such as the skeletal muscle sodium channel (SkM1) operating more effectively at depolarized membrane potentials might restore fast conduction in epicardial border zones and be antiarrhythmic. Computer simulations were done with a modified Hund-Rudy model. Canine myocardial infarcts were created by coronary ligation. Adenovirus expressing SkM1 and green fluorescent protein or green fluorescent protein alone (sham) was injected into epicardial border zones. After 5 to 7 days, dogs were studied with epicardial mapping, programmed premature stimulation in vivo, and cellular electrophysiology in vitro. Infarct size was determined, and tissues were immunostained for SkM1 and green fluorescent protein. In the computational model, modest SkM1 expression preserved fast conduction at potentials as positive as -60 mV; overexpression of SCN5A did not. In vivo epicardial border zone electrograms were broad and fragmented in shams (31.5 +/- 2.3 ms) and narrower in SkM1 (22.6 +/- 2.8 ms; P=0.03). Premature stimulation induced ventricular tachyarrhythmia/fibrillation >60 seconds in 6 of 8 shams versus 2 of 12 SkM1 (P=0.02). Microelectrode studies of epicardial border zones from SkM1 showed membrane potentials equal to that of shams and V(max) greater than that of shams as membrane potential depolarized (P<0.01). Infarct sizes were similar (sham, 30 +/- 2.8%; SkM1, 30 +/- 2.6%; P=0.86). SkM1 expression in injected epicardium was confirmed immunohistochemically. SkM1 increases V(max) of depolarized myocardium and reduces the incidence of inducible sustained ventricular tachyarrhythmia/fibrillation in canine infarcts. Gene therapy to normalize activation by increasing V(max) at depolarized potentials may be a promising antiarrhythmic strategy.

Isolation, characterization and comparison of Atlantic and Chinook salmon growth hormone 1 and 2

BackgroundGrowth hormone (GH) is an important regulator of skeletal growth, as well as other adapted processes in salmonids. The GH gene (gh) in salmonids is represented by duplicated, non-allelic isoforms designated as gh1 and gh2. We have isolated and characterized gh-containing bacterial artificial chromosomes (BACs) of both Atlantic and Chinook salmon (Salmo salar and Oncorhynchus tshawytscha) in order to further elucidate our understanding of the conservation and regulation of these loci.ResultsBACs containing gh1 and gh2 from both Atlantic and Chinook salmon were assembled, annotated, and compared to each other in their coding, intronic, regulatory, and flanking regions. These BACs also contain the genes for skeletal muscle sodium channel oriented in the same direction. The sequences of the genes for interferon alpha-1, myosin alkali light chain and microtubule associated protein Tau were also identified, and found in opposite orientations relative to gh1 and gh2. Viability of each of these genes was examined by PCR. We show that transposon insertions have occurred differently in the promoters of gh, within and between each species. Other differences within the promoters and intronic and 3'-flanking regions of the four gh genes provide evidence that they have distinct regulatory modes and possibly act to function differently and/or during different times of salmonid development.ConclusionA core proximal promoter for transcription of both gh1 and gh2 is conserved between the two species of salmon. Nevertheless, transposon integration and regulatory element differences do exist between the promoters of gh1 and gh2. Additionally, organization of transposon families into the BACs containing gh1 and for the BACs containing gh2, are very similar within orthologous regions, but much less clear conservation is apparent in comparisons between the gh1- and gh2-containing paralogous BACs for the two fish species. This is consistent with the hypothesis that a burst of transposition activity occurred during the speciation events which led to Atlantic and Pacific salmon. The Chinook and other Oncorhynchus GH1s are strikingly different in comparison to the other GHs and this change is not apparent in the surrounding non-coding sequences.

Trans-Channel Interactions in Batrachotoxin-Modified Skeletal Muscle Sodium Channels: Voltage-Dependent Block by Cytoplasmic Amines, and the Influence of μ-Conotoxin GIIIA Derivatives and Permeant Ions

External μ-conotoxins and internal amine blockers inhibit each other's block of voltage-gated sodium channels. We explore the basis of this interaction by measuring the shifts in voltage-dependence of channel inhibition by internal amines induced by two μ-conotoxin derivatives with different charge distributions and net charges. Charge changes on the toxin were made at residue 13, which is thought to penetrate most deeply into the channel, making it likely to have the strongest individual interaction with an internal charged ligand. When an R13Q or R13E molecule was bound to the channel, the voltage dependence of diethylammonium (DEA)-block shifted toward more depolarized potentials (23 mV for R13Q, and 16 mV for R13E). An electrostatic model of the repulsion between DEA and the toxin simulated these data, with a distance between residue 13 of the μ-conotoxin and the DEA-binding site of ∼15 Å. Surprisingly, for tetrapropylammonium, the shifts were only 9 mV for R13Q, and 7 mV for R13E. The smaller shifts associated with R13E, the toxin with a smaller net charge, are generally consistent with an electrostatic interaction. However, the smaller shifts observed for tetrapropylammonium than for DEA suggest that other factors must be involved. Two observations indicate that the coupling of permeant ion occupancy of the channel to blocker binding may contribute to the overall amine-toxin interaction: 1), R13Q binding decreases the apparent affinity of sodium for the conducting pore by ∼4-fold; and 2), increasing external [Na +] decreases block by DEA at constant voltage. Thus, even though a number of studies suggest that sodium channels are occupied by no more than one ion most of the time, measurable coupling occurs between permeant ions and toxin or amine blockers. Such interactions likely determine, in part, the strength of trans-channel, amine-conotoxin interactions.

Trans-Channel Interactions in Batrachotoxin-Modified Rat Skeletal Muscle Sodium Channels: Kinetic Analysis of Mutual Inhibition between μ-Conotoxin GIIIA Derivatives and Amine Blockers

R13X derivatives of μ-conotoxin GIIIA bind externally to single sodium channels and block current incompletely with mean “blocked” durations of several seconds. We studied interactions between two classes of blockers ( μ-conotoxins and amines) by steady state, kinetic analysis of block of BTX-modified Na channels in planar bilayers. The amines cause all-or-none block at a site internal to the selectivity filter. TPrA and DEA block single Na channels with very different kinetics. TPrA induces discrete, all-or-none, blocked events (mean blocked durations, ∼100 ms), whereas DEA produces a concentration-dependent reduction of the apparent single channel amplitude (“fast” block). These distinct modes of action allow simultaneous evaluation of block by TPrA and DEA, showing a classical, competitive interaction between them. The apparent affinity of TPrA decreases with increasing [DEA], based on a decrease in the association rate for TPrA. When an R13X μ-conotoxin derivative and one of the amines are applied simultaneously on opposite sides of the membrane, a mutually inhibitory interaction is observed. Dissociation constants, at +50 mV, for TPrA (∼4 mM) and DEA (∼30 mM) increase by ∼20%–50% when R13E (nominal net charge, +4) or R13Q (+5) is bound. Analysis of the slow blocking kinetics for the two toxin derivatives showed comparable decreases in affinity of the μ-conotoxins in the presence of an amine. Although this mutual inhibition seems to be qualitatively consistent with an electrostatic interaction across the selectivity filter, quantitative considerations raise questions about the mechanistic details of the interaction.

Slow inactivation of the NaV1.4 sodium channel in mammalian cells is impeded by co-expression of the β1 subunit

In response to sustained depolarization or prolonged bursts of activity in spiking cells, sodium channels enter long-lived non-conducting states from which recovery at hyperpolarized potentials occurs over hundreds of milliseconds to seconds. The molecular basis for this slow inactivation remains unknown, although many functional domains of the channel have been implicated. Expression studies in Xenopus oocytes and mammalian cell lines have suggested a role for the accessory beta1 subunit in slow inactivation, but the effects have been variable. We examined the effects of the beta1 subunit on slow inactivation of skeletal muscle (NaV1.4) sodium channels expressed in HEK cells. Co-expression of the beta1 subunit impeded slow inactivation elicited by a 30-s depolarization, such that the voltage dependence was right shifted (depolarized) and recovery was hastened. Mutational studies showed this effect was dependent upon the extracellular Ig-like domain, but was independent of the intracellular C-terminal tail. Furthermore, the beta1 effect on slow inactivation was shown to be independent of the negative coupling between fast and slow inactivation.

The Dominant Cold-SensitiveOut-ColdMutants ofDrosophila melanogasterHave Novel Missense Mutations in the Voltage-Gated Sodium Channel Geneparalytic

Here we report the molecular characterization of Out-cold (Ocd) mutants of Drosophila melanogaster, which produce a dominant, X-linked, cold-sensitive paralytic phenotype. From its initial 1.5-Mb cytological location within 13F1-16A2, P-element and SNP mapping reduced the Ocd critical region to <100 kb and to six candidate genes: hangover, CG9947, CG4420, eIF2a, Rbp2, and paralytic (para). Complementation testing with para null mutations strongly suggests Ocd and para are allelic, as does gene rescue of Ocd semilethality with a wild-type para transgene. Pesticide resistance and electrophysiological phenotypes of Ocd mutants support this conclusion. The para gene encodes a voltage-gated sodium channel. Sequencing the Ocd lines revealed mutations within highly conserved regions of the para coding sequence, in the transmembrane segment S6 of domain III (I1545M and T1551I), and in the linker between domains III and IV (G1571R), the location of the channel inactivation gate. The G1571R mutation is of particular interest as mutations of the orthologous residue (G1306) in the human skeletal muscle sodium channel gene SCN4A are associated with cases of periodic paralysis and myotonia, including the human cold-sensitive disorder paramyotonia congenita. The mechanisms by which sodium channel mutations cause cold sensitivity are not well understood. Therefore, in the absence of suitable vertebrate models, Ocd provides a system in which genetic, molecular, physiological, and behavioral tools can be exploited to determine mechanisms underlying sodium channel periodic paralyses.

High‐affinity blockade of voltage‐operated skeletal muscle and neuronal sodium channels by halogenated propofol analogues

Voltage-operated sodium channels constitute major target sites for local anaesthetic-like action. The clinical use of local anaesthetics is still limited by severe side effects, in particular, arrhythmias and convulsions. These side effects render the search for new local anaesthetics a matter of high interest. We have investigated the effects of three halogenated structural analogues of propofol on voltage-operated human skeletal muscle sodium channels (Na(V)1.4) and the effect of one compound (4-chloropropofol) on neuronal sodium channels (Na(V)1.2) heterologously expressed in human embryonic kidney cell line 293. 4-Iodo-, 4-bromo- and 4-chloropropofol reversibly suppressed depolarization-induced whole-cell sodium inward currents with high potency. The IC(50) for block of resting channels at -150 mV was 2.3, 3.9 and 11.3 microM in Na(V)1.4, respectively, and 29.2 microM for 4-chloropropofol in Na(V)1.2. Membrane depolarization inducing inactivation strongly increased the blocking potency of all compounds. Estimated affinities for the fast-inactivated channel state were 81 nM, 312 nM and 227 nM for 4-iodopropofol, 4-bromopropofol and 4-chloropropofol in Na(V)1.4, and 450 nM for 4-chloropropofol in Na(V)1.2. Recovery from fast inactivation was prolonged in the presence of drug leading to an accumulation of block during repetitive stimulation at high frequencies (100 Hz). Halogenated propofol analogues constitute a novel class of sodium channel-blocking drugs possessing almost 100-fold higher potency compared with the local anaesthetic and anti-arrhythmic drug lidocaine. Preferential drug binding to inactivated channel states suggests that halogenated propofol analogues might be especially effective in suppressing ectopic discharges in a variety of pathological conditions.

Poster Abstract #13: Interactive Voice Response Diary and Objective Myotonia Measurement as Endpoints for Clinical Trials in Nondystrophic Interactive Voice Response Diary and Objective Myotonia Measurement as Endpoints for Clinical Trials in Nondystrophic Myotonia

Background Nondystrophic myotonia (NDM) is a heterogeneous group of neuromuscular disorders caused by mutations in skeletal muscle sodium and chloride channels. There are no established treatments for myotonia, despite the availability of agents that deserve careful study. An outcome measure of myotonia is important for clinical trials. Methods 45 subjects were enrolled from six academic centers across the United States, England, and Canada. Patients were categorized as myotonia congenita (MC), paramyotonia congenita (PMC), and other myotonic disorders (OMD) Three possible myotonia (symptoms/signs) measures were assessed: relaxation time after maximum voluntary isometric contraction of the finger flexors (QMA); myotonic discharges on needle EMG; an Interactive Voice Response Diary (IVR), for which participants called in once a week for up to 8 weeks to rank symptom severity on a scale of 1 to 9 (stiffness, pain, weakness, fatigue) and frequency (1–7 days). Results Initial clinical diagnosis was 20 MC; 16 PMC; 9 OMD. Myotonic discharge potentials were seen in all subjects with no difference in their degree and location among the subtypes. Of 33 participants for whom QMA test results were available, 15 showed a delay in relaxation; however, for subjects with e 2's hand grip opening on clinical exam, 14/16 showed a delay in relaxation on QMA. From IVR data, frequency of symptoms for the total population was stiffness 91%, pain 60%, weakness 56%, and fatigue 65%. Average severity for each symptom was stiffness, 4.1; pain, 4.0; weakness, 4.2; and fatigue, 4.2. Standard deviation of reported symptom severity within subject was stiffness, 1.2; pain, 1.1; weakness, 1.3; and tiredness, 0.9. For participants reporting symptoms for a given week, the average number of days they experienced symptoms was stiffness, 5.2; pain, 5.2; weakness, 4.4; and fatigue, 4.5. Conclusions The IVR data showed consistency in patient self-rated clinical symptoms related to myotonia, which makes this a potentially useful endpoint for future clinical trials. Quantitive myotonia measure is a less sensitive outcome measure, because only minority patients showed abnormal results. This project is supported by NIH grant 5U54RRO19482.

Endotoxin reduces availability of voltage-gated human skeletal muscle sodium channels at depolarized membrane potentials*

Critical illness myopathy is a common cause for difficulties in weaning from the respirator and prolonged rehabilitation of patients recovering from sepsis. Several studies have shown that the primary cause of acute generalized muscle weakness is loss of muscle membrane excitability. This study was designed to investigate a potential direct interaction of lipopolysaccharides from Escherichia coli with voltage-gated human skeletal muscle sodium channels (NaV1.4) in vitro. In vitro laboratory investigation. University laboratory. NaV1.4 sodium channel alpha-subunits stably expressed in human embryonic kidney (HEK293) cells. We investigated the effect of lipopolysaccharide on voltage-dependent sodium channel gating by using two distinct modes of application: 1) acute perfusion (pharmacologic lipopolysaccharide concentrations between 5 ng/mL and 50 microg/mL) in order to establish a concentration-effect relationship; and 2) incubation with a clinically relevant concentration of lipopolysaccharide (300 pg/mL). Lipopolysaccharide did not alter the kinetics of sodium current activation or inactivation when depolarizations were started from hyperpolarized holding potentials. However, when either fast or slow inactivation was induced by membrane depolarization before the test pulse, lipopolysaccharide reversibly reduced channel availability during the test pulse at concentrations of > or = 50 ng/mL revealed by a maximum hyperpolarizing shift of -25 mV in the voltage dependence of fast and slow inactivation, respectively. Incubation with a lipopolysaccharide concentration of 300 pg/mL for 1 hr reproduced the effects on slow but not on fast inactivation. After 20 hrs of low-dose lipopolysaccharide, the peak sodium current was significantly reduced. Our results show that lipopolysaccharide interacts with voltage-gated sodium channels, reducing channel availability at depolarized membrane potentials during acute application, independent of the membrane potential after chronic exposure. These effects may contribute to reduced muscle membrane excitability in sepsis.

Oxidation of multiple methionine residues impairs rapid sodium channel inactivation

Reactive oxygen species (ROS) readily oxidize the sulfur-containing amino acids cysteine and methionine (Met). The impact of Met oxidation on the fast inactivation of the skeletal muscle sodium channel Na(V)1.4 expressed in mammalian cells was studied by applying the Met-preferring oxidant chloramine-T or by irradiating the ROS-producing dye Lucifer Yellow in the patch pipettes. Both interventions dramatically slowed down inactivation of the sodium channels. Replacement of Met in the Ile-Phe-Met inactivation motif with Leu (M1305L) strongly attenuated the oxidizing effect on inactivation but did not eliminate it completely. Mutagenesis of Met1470 in the putative receptor of the inactivation lid also markedly diminished the oxidation sensitivity of the channel, while that of other conserved Met residues in intracellular linkers connecting the membrane-spanning segments (442, 1139, 1154, 1316, 1469) were of minor importance. The results of mutagenesis, assays of other Na(V) channel isoforms (Na(V)1.2, Na(V)1.5, Na(V)1.7), and the kinetics of the oxidation-induced removal of inactivation collectively indicate that multiple Met residues need to be oxidized to completely impair inactivation. This arrangement using multiple Met residues confers a finely graded oxidative modulation of Na(V) channels and allows organisms to adapt to a variety of oxidative stress conditions, such as ischemic reperfusion.

Slow inactivation

Skeletal muscle membrane excitability resides on a razor’s edge. Increasing excitability leads to myotonia. Reducing excitability can lead to paralysis due to membrane inexcitability. By complexly altering membrane excitability, channelopathies can produce phenotypes that are characterized by both hyperexcitability and paralysis. Detailed physiologic studies can sometimes explain the complex phenotypes produced by specific channelopathies. In this issue of Neurology ®, Webb and Cannon1 provide a cogent explanation for the genesis of a phenotype of myotonia at warm temperature and cold-induced paralysis that is associated with the P1158S mutation of the skeletal muscle sodium channel, NaV1.4. Skeletal muscle channelopathies are fascinating because they illuminate the connection between basic physiology and clinical neurology. The channelopathies are natural experiments that enable us to explore how altering the function of a channel changes membrane excitability. Nobel laureates Hodgkin and Huxley2 opened the modern age of membrane physiology more than a half-century ago through a series of elegant experiments that demonstrated that the action potential in the giant axon of a squid was produced by an interplay between voltage-gated …

Targeted mutation of mouse skeletal muscle sodium channel produces myotonia and potassium-sensitive weakness

Hyperkalemic periodic paralysis (HyperKPP) produces myotonia and attacks of muscle weakness triggered by rest after exercise or by K+ ingestion. We introduced a missense substitution corresponding to a human familial HyperKPP mutation (Met1592Val) into the mouse gene encoding the skeletal muscle voltage-gated Na+ channel NaV1.4. Mice heterozygous for this mutation exhibited prominent myotonia at rest and muscle fiber-type switching to a more oxidative phenotype compared with controls. Isolated mutant extensor digitorum longus muscles were abnormally sensitive to the Na+/K+ pump inhibitor ouabain and exhibited age-dependent changes, including delayed relaxation and altered generation of tetanic force. Moreover, rapid and sustained weakness of isolated mutant muscles was induced when the extracellular K+ concentration was increased from 4 mM to 10 mM, a level observed in the muscle interstitium of humans during exercise. Mutant muscle recovered from stimulation-induced fatigue more slowly than did control muscle, and the extent of recovery was decreased in the presence of high extracellular K+ levels. These findings demonstrate that expression of the Met1592ValNa+ channel in mouse muscle is sufficient to produce important features of HyperKPP, including myotonia, K+-sensitive paralysis, and susceptibility to delayed weakness during recovery from fatigue.

Constrained analogues of tocainide as potent skeletal muscle sodium channel blockers towards the development of antimyotonic agents

1-Benzyl- N-(2,6-dimethylphenyl)piperidine-3-carboxamide and 4-benzyl- N-(2,6-dimethylphenyl)piperazine-2-carboxamide, two conformationally restricted analogues of tocainide, were designed and synthesized as voltage-gated skeletal muscle sodium channel blockers. They showed, with respect to tocainide, a marked increase in both potency and use-dependent block.

ChemInform Abstract: Pilsicainide and Its Oxymethylene Analogue: Facile Alternative Syntheses and in vitro Testing on Human Skeletal Muscle Sodium Channels.

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Structure/Function Characterization of μ-Conotoxin KIIIA, an Analgesic, Nearly Irreversible Blocker of Mammalian Neuronal Sodium Channels

Structure/Function Characterization of μ-Conotoxin KIIIA, an Analgesic, Nearly Irreversible Blocker of Mammalian Neuronal Sodium Channels