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Nature Reviews. Neuroscience Mar 2021The voltage-gated sodium channel α-subunit genes comprise a highly conserved gene family. Mutations of three of these genes, SCN1A, SCN2A and SCN8A, are responsible for... (Review)
Review
The voltage-gated sodium channel α-subunit genes comprise a highly conserved gene family. Mutations of three of these genes, SCN1A, SCN2A and SCN8A, are responsible for a significant burden of neurological disease. Recent progress in identification and functional characterization of patient variants is generating new insights and novel approaches to therapy for these devastating disorders. Here we review the basic elements of sodium channel function that are used to characterize patient variants. We summarize a large body of work using global and conditional mouse mutants to characterize the in vivo roles of these channels. We provide an overview of the neurological disorders associated with mutations of the human genes and examples of the effects of patient mutations on channel function. Finally, we highlight therapeutic interventions that are emerging from new insights into mechanisms of sodium channelopathies.
Topics: Animals; Channelopathies; Humans; Mutation; NAV1.1 Voltage-Gated Sodium Channel; NAV1.2 Voltage-Gated Sodium Channel; NAV1.6 Voltage-Gated Sodium Channel; Neurodevelopmental Disorders; Sodium Channels; Voltage-Gated Sodium Channels
PubMed: 33531663
DOI: 10.1038/s41583-020-00418-4 -
Cell Jan 2020Voltage-gated sodium channel Na1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of Na1.5 at 3.2-3.5 Å resolution. Na1.5...
Voltage-gated sodium channel Na1.5 generates cardiac action potentials and initiates the heartbeat. Here, we report structures of Na1.5 at 3.2-3.5 Å resolution. Na1.5 is distinguished from other sodium channels by a unique glycosyl moiety and loss of disulfide-bonding capability at the Naβ subunit-interaction sites. The antiarrhythmic drug flecainide specifically targets the central cavity of the pore. The voltage sensors are partially activated, and the fast-inactivation gate is partially closed. Activation of the voltage sensor of Domain III allows binding of the isoleucine-phenylalanine-methionine (IFM) motif to the inactivation-gate receptor. Asp and Ala, in the selectivity motif DEKA, line the walls of the ion-selectivity filter, whereas Glu and Lys are in positions to accept and release Na ions via a charge-delocalization network. Arrhythmia mutation sites undergo large translocations during gating, providing a potential mechanism for pathogenic effects. Our results provide detailed insights into Na1.5 structure, pharmacology, activation, inactivation, ion selectivity, and arrhythmias.
Topics: Animals; Cell Line; HEK293 Cells; Heart; Humans; Ion Channel Gating; Membrane Potentials; NAV1.5 Voltage-Gated Sodium Channel; Patch-Clamp Techniques; Rats; Sodium; Sodium Channels; Structure-Activity Relationship; Voltage-Gated Sodium Channels
PubMed: 31866066
DOI: 10.1016/j.cell.2019.11.041 -
Nature Dec 2006The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the...
The complete inability to sense pain in an otherwise healthy individual is a very rare phenotype. In three consanguineous families from northern Pakistan, we mapped the condition as an autosomal-recessive trait to chromosome 2q24.3. This region contains the gene SCN9A, encoding the alpha-subunit of the voltage-gated sodium channel, Na(v)1.7, which is strongly expressed in nociceptive neurons. Sequence analysis of SCN9A in affected individuals revealed three distinct homozygous nonsense mutations (S459X, I767X and W897X). We show that these mutations cause loss of function of Na(v)1.7 by co-expression of wild-type or mutant human Na(v)1.7 with sodium channel beta(1) and beta(2) subunits in HEK293 cells. In cells expressing mutant Na(v)1.7, the currents were no greater than background. Our data suggest that SCN9A is an essential and non-redundant requirement for nociception in humans. These findings should stimulate the search for novel analgesics that selectively target this sodium channel subunit.
Topics: Base Sequence; Cell Line; Chromosomes, Human, Pair 2; Female; Humans; Male; Molecular Sequence Data; Mutation; NAV1.7 Voltage-Gated Sodium Channel; Pain; Pain Insensitivity, Congenital; Patch-Clamp Techniques; Pedigree; Phenotype; Physical Chromosome Mapping; Sodium Channels
PubMed: 17167479
DOI: 10.1038/nature05413 -
Proceedings of the National Academy of... Jan 2023Voltage-gated sodium channel Na1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na1.6 may lead to epilepsy and other...
Voltage-gated sodium channel Na1.6 plays a crucial role in neuronal firing in the central nervous system (CNS). Aberrant function of Na1.6 may lead to epilepsy and other neurological disorders. Specific inhibitors of Na1.6 thus have therapeutic potentials. Here we present the cryo-EM structure of human Na1.6 in the presence of auxiliary subunits β1 and fibroblast growth factor homologous factor 2B (FHF2B) at an overall resolution of 3.1 Å. The overall structure represents an inactivated state with closed pore domain (PD) and all "up" voltage-sensing domains. A conserved carbohydrate-aromatic interaction involving Trp302 and Asn326, together with the β1 subunit, stabilizes the extracellular loop in repeat I. Apart from regular lipids that are resolved in the EM map, an unprecedented Y-shaped density that belongs to an unidentified molecule binds to the PD, revealing a potential site for developing Na1.6-specific blockers. Structural mapping of disease-related Na1.6 mutations provides insights into their pathogenic mechanism.
Topics: Humans; Cryoelectron Microscopy; Voltage-Gated Sodium Channels; NAV1.7 Voltage-Gated Sodium Channel; NAV1.6 Voltage-Gated Sodium Channel; NAV1.1 Voltage-Gated Sodium Channel; NAV1.5 Voltage-Gated Sodium Channel; NAV1.2 Voltage-Gated Sodium Channel
PubMed: 36696443
DOI: 10.1073/pnas.2220578120 -
Cellular and Molecular Life Sciences :... Apr 2012Voltage-gated sodium channels mediate inward current of action potentials upon membrane depolarization of excitable cells. The initial transient sodium current is... (Review)
Review
Voltage-gated sodium channels mediate inward current of action potentials upon membrane depolarization of excitable cells. The initial transient sodium current is restricted to milliseconds through three distinct channel-inactivating and blocking mechanisms. All pore-forming alpha subunits of sodium channels possess structural elements mediating fast inactivation upon depolarization and recovery within milliseconds upon membrane repolarization. Accessory subunits modulate fast inactivation dynamics, but these proteins can also limit current by contributing distinct inactivation and blocking particles. A-type isoforms of fibroblast growth factor homologous factors (FHFs) bear a particle that induces long-term channel inactivation, while sodium channel subunit Navβ4 employs a blocking particle that rapidly dissociates upon membrane repolarization to generate resurgent current. Despite their different physiological functions, the FHF and Navβ4 particles have similarity in amino acid composition and mechanisms for docking within sodium channels. The three competing channel-inactivating and blocking processes functionally interact to regulate a neuron's intrinsic excitability.
Topics: Action Potentials; Animals; Humans; Ion Channel Gating; Sodium Channel Blockers; Sodium Channels
PubMed: 21947499
DOI: 10.1007/s00018-011-0832-1 -
Cardiovascular Therapeutics Oct 2010Cardiac voltage-gated sodium channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of sodium ions through these ion channels is... (Review)
Review
Cardiac voltage-gated sodium channels are transmembrane proteins located in the cell membrane of cardiomyocytes. Influx of sodium ions through these ion channels is responsible for the initial fast upstroke of the cardiac action potential. This inward sodium current thus triggers the initiation and propagation of action potentials throughout the myocardium and consequently plays a central role in excitability of myocardial cells and proper conduction of the electrical impulse within the heart. The importance of sodium channels for normal cardiac electrical activity is emphasized by the occurrence of potentially lethal arrhythmias in the setting of inherited and acquired sodium channel disease. During common pathological conditions such as myocardial ischemia and heart failure, altered sodium channel function causes conduction disturbances and ventricular arrhythmias. In addition, sodium channel dysfunction caused by mutations in the SCN5A gene, encoding the major sodium channel in heart, is associated with a number of arrhythmia syndromes. Here, we provide an overview of the structure and function of the cardiac sodium channel, the clinical and biophysical characteristics of inherited and acquired sodium channel dysfunction, and the (limited) therapeutic options for the treatment of cardiac sodium channel disease.
Topics: Action Potentials; Arrhythmias, Cardiac; Genetic Predisposition to Disease; Humans; Muscle Proteins; Mutation; Myocytes, Cardiac; NAV1.5 Voltage-Gated Sodium Channel; Protein Conformation; Sodium Channels; Structure-Activity Relationship
PubMed: 20645984
DOI: 10.1111/j.1755-5922.2010.00210.x -
Neuron Dec 2006Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, OMIM 167400), is an inherited disease causing intense burning rectal, ocular, and...
Paroxysmal extreme pain disorder (PEPD), previously known as familial rectal pain (FRP, OMIM 167400), is an inherited disease causing intense burning rectal, ocular, and submandibular pain and flushing. Fertleman et al. (this issue of Neuron) show that mutations in SCN9A, the gene encoding the sodium channel Na(V)1.7 channels, are responsible for this syndrome. Together with earlier work implicating a distinct class of functional mutations in SCN9A in a distinct inherited pain syndrome, these results point to Na(V)1.7 channels as key players in signaling nociceptive information and as a potential target for drug therapy of chronic pain.
Topics: Humans; Mutation; NAV1.7 Voltage-Gated Sodium Channel; Neuralgia; Rectal Diseases; Sodium Channels
PubMed: 17145494
DOI: 10.1016/j.neuron.2006.11.017 -
Pain Jun 2023Transient voltage-gated sodium currents are essential for the initiation and conduction of action potentials in neurons and cardiomyocytes. The amplitude and duration of...
Transient voltage-gated sodium currents are essential for the initiation and conduction of action potentials in neurons and cardiomyocytes. The amplitude and duration of sodium currents are tuned by intracellular fibroblast growth factor homologous factors (FHFs/iFGFs) that associate with the cytoplasmic tails of voltage-gated sodium channels (Na v s), and genetic ablation of Fhf genes disturbs neurological and cardiac functions. Among reported phenotypes, Fhf2null mice undergo lethal hyperthermia-induced cardiac conduction block attributable to the combined effects of FHF2 deficiency and elevated temperature on the cardiac sodium channel (Na v 1.5) inactivation rate. Fhf2null mice also display a lack of heat nociception, while retaining other somatosensory capabilities. Here, we use electrophysiological and computational methods to show that the heat nociception deficit can be explained by the combined effects of elevated temperature and FHF2 deficiency on the fast inactivation gating of Na v 1.7 and tetrodotoxin-resistant sodium channels expressed in dorsal root ganglion C fibers. Hence, neurological and cardiac heat-associated deficits in Fhf2null mice derive from shared impacts of FHF deficiency and temperature towards Na v inactivation gating kinetics in distinct tissues.
Topics: Animals; Mice; Ganglia, Spinal; Hot Temperature; Nociception; Sodium; Sodium Channels; Temperature; Tetrodotoxin
PubMed: 36607284
DOI: 10.1097/j.pain.0000000000002822 -
Cell Jun 2016While some neurons are tuned to integrate fast and precisely timed inputs, others set behavioral states on much slower timescales. In this issue of Cell, Branco et al....
While some neurons are tuned to integrate fast and precisely timed inputs, others set behavioral states on much slower timescales. In this issue of Cell, Branco et al. demonstrate that body weight is regulated by hypothalamic neurons using a highly effective form of slow synaptic integration, which is mediated by the voltage gated sodium channel Nav1.7.
Topics: NAV1.7 Voltage-Gated Sodium Channel; Neurons; Sodium Channels
PubMed: 27315473
DOI: 10.1016/j.cell.2016.06.005 -
The Journal of Physiology Mar 2023
Topics: Humans; Heart; Long QT Syndrome; Sodium Channels; NAV1.5 Voltage-Gated Sodium Channel; Myocytes, Cardiac
PubMed: 36744524
DOI: 10.1113/JP284172