Sodium Channelopathies of Skeletal Muscle and Brain

2021 ◽  
Author(s):  
Massimo Mantegazza ◽  
Sandrine Cestèle ◽  
William Catterall
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channels ◽  
Cell Biology ◽  
Periodic Paralysis ◽  
Mouse Genetics ◽  
Ion Conductance ◽  
Voltage Gated Sodium Channels ◽  
Wide Range ◽  
Voltage Dependent ◽  
Periodic Paralyses

Voltage-gated sodium channels initiate action potentials in nerve, skeletal muscle, and other electrically excitable cells. Mutations in them cause a wide range of diseases. These channelopathy mutations affect every aspect of sodium channel function, including voltage sensing, voltage-dependent activation, ion conductance, fast and slow inactivation, and both biosynthesis and assembly. Mutations that cause different forms of periodic paralysis in skeletal muscle were discovered first and have provided a template for understanding structure, function, and pathophysiology at the molecular level. More recent work has revealed multiple sodium channelopathies in the brain. Here we review the well-characterized genetics and pathophysiology of the periodic paralyses of skeletal muscle, and then use this information as a foundation for advancing our understanding of mutations in the structurally homologous a subunits of brain sodium channels that cause epilepsy, migraine, autism, and related co-morbidities. We include studies based on molecular and structural biology, cell biology and physiology, pharmacology, and mouse genetics. Our review reveals unexpected connections among these different types of sodium channelopathies.

scholarly journals A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
Mohammad-Reza Ghovanloo ◽  
Mena Abdelsayed ◽  
Colin H. Peters ◽  
Peter C. Ruben
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channels ◽  
Periodic Paralysis ◽  
Ph Sensitivity ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels

2017 ◽  
Author(s):  
Mohammad-Reza Ghovanloo ◽  
Mena Abdelsayed ◽  
Colin H. Peters ◽  
Peter C. Ruben
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channels ◽  
Muscular Contraction ◽  
Periodic Paralysis ◽  
Ph Sensitivity ◽  
Voltage Gated ◽  
Blood Ph ◽  
Voltage Gated Sodium Channels ◽  
Missense Mutant ◽  
Electrical Signaling

ABSTRACTSkeletal muscle channelopathies, many of which are inherited as autosomal dominant mutations, include both myotonia and periodic paralysis. Myotonia is defined by a delayed relaxation after muscular contraction, whereas periodic paralysis is defined by episodic attacks of weakness. One sub-type of periodic paralysis, known as hypokalemic periodic paralysis (hypoPP), is associated with low potassium levels. Interestingly, the P1158S missense mutant, located in the third domain S4-S5 linker of the ‘‘skeletal muscle’’ voltage-gated sodium channel, Nav1.4, has been implicated in causing both myotonia and hypoPP. A common trigger for these conditions is physical activity. We previously reported that Nav1.4 is relatively insensitive to changes in extracellular pH compared to Nav1.2 and Nav1.5. Given that intense exercise is often accompanied by blood acidosis, we decided to test whether changes in pH would push gating in P1158S towards either phenotype. Our results indicate that, unlike in WT Nav1.4, low pH depolarizes the voltage-dependence of activation and steady-state fast inactivation, decreases current density, and increases late currents in P1185S. Thus, P1185S turns the normally pH-insensitive Nav1.4 into a proton-sensitive channel. Using action potential modeling we also predict a pH-to-phenotype correlation in patients with P1158S. We conclude that activities which alter blood pH may trigger myotonia or periodic paralysis in P1158S patients.SIGNIFICANCE STATEMENTVoltage-gated sodium channels (Nav) contribute to the physiology and pathophysiology of electrical signaling in excitable cells. Nav subtypes are expressed in a tissue-specific manner, thus they respond differently to physiological modulators. For instance, the cardiac subtype, Nav1.5, can be modified by changes in blood pH; however, the skeletal muscle subtype, Nav1.4, is mostly pH-insensitive. Nav1.4 mutants can mostly cause either hyper-or hypo-excitability in skeletal muscles, leading to conditions such as myotonia or periodic paralysis. P1158S uniquely causes both phenotypes. This study investigates pH-sensitivity in P1158S, and describes how physiological pH changes can push P1158S to cause myotonia and periodic paralysis.

scholarly journals 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

2008 ◽  
Vol 95 (9) ◽  
pp. 4277-4288 ◽  
Author(s):  
Evgeny Pavlov ◽  
Tatiana Britvina ◽  
Jeff R. McArthur ◽  
Quanli Ma ◽  
Iván Sierralta ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channels ◽  
Voltage Dependent ◽  
Channel Interactions

scholarly journals Tracking S4 movement by gating pore currents in the bacterial sodium channel NaChBac

2014 ◽  
Vol 144 (2) ◽  
pp. 147-157 ◽  
Author(s):  
Tamer M. Gamal El-Din ◽  
Todd Scheuer ◽  
William A. Catterall
Keyword(s):  
Membrane Potential ◽  
Sodium Channel ◽  
Sodium Channels ◽  
Voltage Dependence ◽  
Periodic Paralysis ◽  
Membrane Potentials ◽  
Structural Basis ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Gating Charges

Voltage-gated sodium channels mediate the initiation and propagation of action potentials in excitable cells. Transmembrane segment S4 of voltage-gated sodium channels resides in a gating pore where it senses the membrane potential and controls channel gating. Substitution of individual S4 arginine gating charges (R1–R3) with smaller amino acids allows ionic currents to flow through the mutant gating pore, and these gating pore currents are pathogenic in some skeletal muscle periodic paralysis syndromes. The voltage dependence of gating pore currents provides information about the transmembrane position of the gating charges as S4 moves in response to membrane potential. Here we studied gating pore current in mutants of the homotetrameric bacterial sodium channel NaChBac in which individual arginine gating charges were replaced by cysteine. Gating pore current was observed for each mutant channel, but with different voltage-dependent properties. Mutating the first (R1C) or second (R2C) arginine to cysteine resulted in gating pore current at hyperpolarized membrane potentials, where the channels are in resting states, but not at depolarized potentials, where the channels are activated. Conversely, the R3C gating pore is closed at hyperpolarized membrane potentials and opens with channel activation. Negative conditioning pulses revealed time-dependent deactivation of the R3C gating pore at the most hyperpolarized potentials. Our results show sequential voltage dependence of activation of gating pore current from R1 to R3 and support stepwise outward movement of the substituted cysteines through the narrow portion of the gating pore that is sealed by the arginine side chains in the wild-type channel. This pattern of voltage dependence of gating pore current is consistent with a sliding movement of the S4 helix through the gating pore. Through comparison with high-resolution models of the voltage sensor of bacterial sodium channels, these results shed light on the structural basis for pathogenic gating pore currents in periodic paralysis syndromes.

Spatiotemporal magnetic fields enhance cytosolic Ca 2+ levels and induce actin polymerization via activation of voltage-gated sodium channels in skeletal muscle cells

Biomaterials ◽  
2018 ◽  
Vol 163 ◽  
pp. 174-184 ◽  
Author(s):  
Mónica Rubio Ayala ◽  
Tatiana Syrovets ◽  
Susanne Hafner ◽  
Vitalii Zablotskii ◽  
Alexandr Dejneka ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Magnetic Fields ◽  
Sodium Channels ◽  
Actin Polymerization ◽  
Muscle Cells ◽  
Skeletal Muscle Cells ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol

2002 ◽  
Vol 19 (8) ◽  
pp. 571-579 ◽  
Author(s):  
G. Haeseler ◽  
D. Maue ◽  
J. Grosskreutz ◽  
J. Bufler ◽  
B. Nentwig ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channels ◽  
Voltage Dependent

scholarly journals Point-Mutations in Skeletal Muscle Voltage-Gated Sodium Channels Confer Resistance to Tetrodotoxin: But at a Cost?

2016 ◽  
Vol 110 (3) ◽  
pp. 436a-437a ◽  
Author(s):  
Robert E. del Carlo ◽  
Normand Leblanc ◽  
Edmund D. Brodie ◽  
Chis R. Feldman
Keyword(s):  
Skeletal Muscle ◽  
Sodium Channels ◽  
Point Mutations ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels

scholarly journals Batrachotoxin-modified sodium channels in planar lipid bilayers. Characterization of saxitoxin- and tetrodotoxin-induced channel closures.

1987 ◽  
Vol 89 (6) ◽  
pp. 873-903 ◽  
Author(s):  
W N Green ◽  
L B Weiss ◽  
O S Andersen
Keyword(s):  
Binding Site ◽  
Lipid Bilayers ◽  
Sodium Channels ◽  
Conformational Changes ◽  
Single Channel ◽  
Planar Lipid Bilayers ◽  
Net Charge ◽  
Toxin Binding ◽  
Wide Range ◽  
Voltage Dependent

The guanidinium toxin-induced inhibition of the current through voltage-dependent sodium channels was examined for batrachotoxin-modified channels incorporated into planar lipid bilayers that carry no net charge. To ascertain whether a net negative charge exists in the vicinity of the toxin-binding site, we studied the channel closures induced by tetrodotoxin (TTX) and saxitoxin (STX) over a wide range of [Na+]. These toxins carry charges of +1 and +2, respectively. The frequency and duration of the toxin-induced closures are voltage dependent. The voltage dependence was similar for STX and TTX, independent of [Na+], which indicates that the binding site is located superficially at the extracellular surface of the sodium channel. The toxin dissociation constant, KD, and the rate constant for the toxin-induced closures, kc, varied as a function of [Na+]. The Na+ dependence was larger for STX than for TTX. Similarly, the addition of tetraethylammonium (TEA+) or Zn++ increased KD and decreased kc more for STX than for TTX. These differential effects are interpreted to arise from changes in the electrostatic potential near the toxin-binding site. The charges giving rise to this potential must reside on the channel since the bilayers had no net charge. The Na+ dependence of the ratios KDSTX/KDTTX and kcSTX/kcTTX was used to estimate an apparent charge density near the toxin-binding site of about -0.33 e X nm-2. Zn++ causes a voltage-dependent block of the single-channel current, as if Zn++ bound at a site within the permeation path, thereby blocking Na+ movement. There was no measurable interaction between Zn++ at its blocking site and STX or TTX at their binding site, which suggests that the toxin-binding site is separate from the channel entrance. The separation between the toxin-binding site and the Zn++ blocking site was estimated to be at least 1.5 nm. A model for toxin-induced channel closures is proposed, based on conformational changes in the channel subsequent to toxin binding.

scholarly journals Voltage-Gated Sodium Channels: A Prominent Target of Marine Toxins

Marine Drugs ◽  
2021 ◽  
Vol 19 (10) ◽  
pp. 562
Author(s):  
Rawan Mackieh ◽  
Rita Abou-Nader ◽  
Rim Wehbe ◽  
César Mattei ◽  
Christian Legros ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Physiological Role ◽  
Supporting Cell ◽  
Cone Snail ◽  
Marine Toxins ◽  
Marine Animals ◽  
Communication Signals ◽  
Voltage Gated ◽  
Voltage Gated Sodium Channels ◽  
Wide Range

Voltage-gated sodium channels (VGSCs) are considered to be one of the most important ion channels given their remarkable physiological role. VGSCs constitute a family of large transmembrane proteins that allow transmission, generation, and propagation of action potentials. This occurs by conducting Na+ ions through the membrane, supporting cell excitability and communication signals in various systems. As a result, a wide range of coordination and physiological functions, from locomotion to cognition, can be accomplished. Drugs that target and alter the molecular mechanism of VGSCs’ function have highly contributed to the discovery and perception of the function and the structure of this channel. Among those drugs are various marine toxins produced by harmful microorganisms or venomous animals. These toxins have played a key role in understanding the mode of action of VGSCs and in mapping their various allosteric binding sites. Furthermore, marine toxins appear to be an emerging source of therapeutic tools that can relieve pain or treat VGSC-related human channelopathies. Several studies documented the effect of marine toxins on VGSCs as well as their pharmaceutical applications, but none of them underlined the principal marine toxins and their effect on VGSCs. Therefore, this review aims to highlight the neurotoxins produced by marine animals such as pufferfish, shellfish, sea anemone, and cone snail that are active on VGSCs and discuss their pharmaceutical values.

Sign in / Sign up

Export Citation Format

Share Document