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Voltage-gated sodium channels are responsible for action potential initiation and propagation in excitable cells, including nerve, muscle, and neuroendocrine cell types. They are also expressed at low levels in nonexcitable cells, where their physiological role is unclear. Sodium channels are the founding members of the ion channel superfamily in terms of their discovery as a protein and determination of their amino acid sequence. 
Sodium channels were the first members of the ion channel superfamily to be discovered; the superfamily also includes voltage-gated K+ channels, voltage-gated Ca2+ channels, Trp-related channels (a diverse family permeable to various cations) and cyclic-nucleotide-gated channels (Hille B: Ion Channels of Excitable Membranes. Sunderland, MA: Sinauer Associates Inc; 2001. ). But in evolution, the sodium channel family is the most recent of the voltage-gated ion channels to have arisen, having evolved from similarly structured Ca2+ channels that contain four homologous domains. Ca2+ channels, in turn, probably arose by two rounds of gene duplication from the ancestors of K+ and cyclic-nucleotide-gated channels, which form functional channels as tetramers of single-domain subunits. The appearance of four-domain sodium channels coincided with evolution of metazoans that had specialized neurons . Although ‘classical’ four-domain sodium channels have not been identified from prokaryotes, a recent report has identified a bacterial sodium channel (Figure 1c in ) in the salt-loving bacterium Bacillus halodurans . This single-domain voltage-dependent sodium channel, which also has sequence and pharmacological characteristics resembling those of Ca2+ channels, opens up the intriguing possibility that it is similar to the ancestral single-domain channel from which the Ca2+ and Na+ channels have arisen. (Whole paragraph from Yu .) For more detailed information about the adaptive evolution of voltage-gated sodium channels see Zakon (2012) .
In mammals nine functionally expressed voltage-gated sodium channel (Nav1.1-Nav1.9, VGSC) are encoded by 11 genes (SCN1A-SCN11A) . VGSC consist in: i) Alfa-subunits organized into four homologous domains (DI-DIV) composed of six transmembrane segments: segments 1-4 form the voltage sensor while segments 5-6 and the linker P-loop compose the pore region ii) Beta-subunits that act as regulatory molecules. The SCN7A/Nax gene encodes an atypical sodium channel, named ‘Nax’ that is considered to be a descendant of the voltage-gated sodium channel, although it is not regulated by the membrane’s voltage as in the other channels of the sodium channel family . Four sodium channel isoforms (Nav1.1, Nav1.2, Nav1.3 and Nav1.6) are highly expressed in the central nervous system. Two isoforms are abundant in muscle: Nav1.4 in adult skeletal muscle and Nav1.5 in embryonic and denervated skeletal muscle and heart muscle. Finally, Nav1.7, Nav1.8 and Nav1.9, are expressed primarily in the peripheral nervous system .
For a phylogenetic tree and nomenclature/classification, see Catterall .
: Sodium channel
According to the convention of the International Union of Pharmacologists, the nomenclature of sodium channels (for example, Nav1.1) consists of the chemical symbol of the principal permeating ion (Na) and the principal physiological regulator (voltage, subscript) followed by a number indicating the gene subfamily and a decimal that separates the number assigned to specific channel isoforms .
From Catterall : All of the pharmacological agents that act on sodium channels have receptor sites on the alpha subunits. At least six distinct receptor sites for neurotoxins and one receptor site for local anesthetics and related drugs have been identified ; Table 1 in . Neurotoxin receptor site 1 binds the nonpeptide pore blockers tetrodotoxin and saxitoxin and the peptide pore blocker mu-conotoxin , , .
The two muscle sodium channel isoforms can easily be distinguished from each other and from the CNS isoforms on the basis of toxin sensitivity :
The receptor sites for these toxins are formed by amino acid residues in the pore loops and immediately on the extracellular side of the pore loops at the outer end of the pore. Neurotoxin receptor site 2 binds a family of lipid-soluble toxins, including batrachotoxin, veratridine, aconitine, and grayanotoxin, which enhance activation of sodium channels. Photoaffinity labeling and mutagenesis studies implicate transmembrane segments IS6 and IVS6 in the receptor site for batrachotoxin . Neurotoxin receptor site 3 binds the alpha-scorpion toxins and sea anemone toxins, which slow the coupling of sodium channel activation to inactivation. These peptide toxins bind to a complex receptor site that includes the S3-S4 loop at the outer end of the S4 segment in domain IV . Neurotoxin receptor site 4 binds the beta-scorpion toxins, which enhance activation of the channels. The receptor site for the beta-scorpion toxins includes the S3-S4 loop at the extracellular end of the voltage-sensing S4 segments in domain II (Cestele and Catterall, 2000). Neurotoxin receptor site 5 binds the complex polyether toxins brevetoxin and ciguatoxin, which are made by dinoflagellates and cause toxic red tides in warm ocean waters . Transmembrane segments IS6 and IVS5 are implicated in brevetoxin binding from photoaffinity labeling studies .
Neurotoxin receptor site 6 binds delta-conotoxins, which slow the rate of inactivation like the alpha-scorpion toxins. The location of neurotoxin receptor site 6 is unknown. Finally, the local anesthetics and related antiepileptic and antiarrhythmic drugs bind to overlapping receptor sites located in the inner cavity of the pore of the sodium channel . Amino acid residues in the S6 segments from at least three of the four domains contribute to this complex drug receptor site, with the IVS6 segment playing the dominant role. Tables 2 through 10 in  summarize the major molecular, physiological, and pharmacological properties for each of the nine sodium channels that have been functionally expressed. Quantitative data are included for voltage dependence of activation and inactivation, single-channel conductance, and binding of drugs and neurotoxins, focusing on those agents that are widely used and diagnostic of channel identity and function.
The gene expression of Nav channels present in the DRG are regulated by 17β-Estradiol and this may be an important mechanism of pain regulation .
Sodium channels consist of a large α subunit that associates with other proteins, such as β subunits. An α subunit forms the core of the channel and is functional on its own. When the α subunit protein is expressed by a cell, it is able to form channels that conduct Na+ in a voltage-gated way, even if β subunits or other known modulating proteins are not expressed. When accessory proteins assemble with α subunits, the resulting complex can display altered voltage dependence and cellular localization.
The α-subunit has four repeat domains, labeled I through IV, each containing six membrane-spanning regions, labeled S1 through S6. The highly conserved S4 region acts as the channel's voltage sensor. The voltage sensitivity of this channel is due to positive amino acids located at every third position. When stimulated by a change in transmembrane voltage, this region moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions. The ions are conducted through a pore, which can be broken into two regions. The more external (i.e., more extracellular) portion of the pore is formed by the "P-loops" (the region between S5 and S6) of the four domains. This region is the most narrow part of the pore and is responsible for its ion selectivity. The inner portion (i.e., more cytoplasmic) of the pore is formed by the combined S5 and S6 regions of the four domains. The region linking domains III and IV is also important for channel function. This region plugs the channel after prolonged activation, inactivating it.
Many of the mammalian sodium channel alfa-subunits are associated with accessory beta-subunits in vivo. The beta-1 subunit is noncovalently attached to the alfa-subunit, and the beta-2 subunit is covalently linked to the alfa-subunit by disulfide bonds. Channels in the adult CNS are associated with both beta-1 and beta-2 subunits, and channels in adult skeletal muscle are associated with just beta-1. In addition, cDNA clones encoding a beta-3 subunit have been isolated. The sequences of the three beta-subunits are not homologous, but they are all clearly related based on the phylogenetic tree. Each of the beta subunit sequences predicts a protein with an amino-terminal signal sequence and single membrane-spanning region, indicative of an extracellular amino terminus. All three beta-subunits contain immunoglobulin-like folds similar to those found in neural cell adhesion molecules. Co-expression of the beta-1 subunit with many of the alfa-subunits in Xenopus oocytes modulates the electrophysiological properties of the channel, including accelerating inactivation and shifting the voltage-dependence of steady-state inactivation in the negative direction. Co-expression of the beta-3 subunit modulates gating of the alfa-subunit sodium channels to a lesser extent than does co-expression of beta-1, and co-expression of the beta-2 subunit modulates alfa-subunit gating the least of the beta-subunits. The beta-subunits are also important for sodium channel interactions with cellular proteins. The beta-2 subunit significantly increases membrane capacitance, which may indicate that it is involved in insertion of the channels into the cellular membrane. Both beta-1 and beta-2 interact with the extracellular matrix proteins tenascin-C and tenascin-R, suggesting that the proteins may function as cellular adhesion molecules. Consistent with this hypothesis, both beta-1 and beta-2 subunits recruit ankyrin to sites of cell-cell contact, and this recruitment requires the cytoplasmic domains of the subunits.
The pore of sodium channels contains a selectivity filter made of negatively charged amino acid residues, which attract the positive Na+ ion and keep out negatively charged ions such as chloride. The cations flow into a more constricted part of the pore that is 0.3 by 0.5 nm wide, which is just large enough to allow a single Na+ ion with a water molecule associated to pass through. The larger K+ ion cannot fit through this area. Differently sized ions also cannot interact as well with the negatively charged glutamic acid residues that line the pore.
The density of Na+ channels in the AIS of cortical layer 5 pyramidal neurons is high (on average 50-fold higher than the density at the soma and proximal dendrites). A high AIS Na+ channel density (2,500 pS per square micro meter) is required to account for experimental observations on the rate of rise of axonal action potentials, as well as on action potential initiation and backpropagation. .
Central Nervous System Channels 
Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are expressed abundantly in the CNS. Nav1.5 was not originally detected in brain, but more sensitive approaches have demonstrated expression in the piriform cortex and subcortical limbic nuclei, which may explain the observation of sodium currents in the entorhinal cortex, with properties similar to those in cardiac muscle. Specifically, Nav1.1 was detected at high levels in the cell bodies within the hippocampus, cerebellum, spinal cord, brainstem, cortex, substantia nigra, and caudate. In the cerebellum, Nav1.1 is detectable in Purkinje cells but not in granule cells. Nav1.2 was observed at high levels in the axons within the globus pallidus, hippocampus, and thalamus. There is no rostral-caudal gradient of Nav1.6 mRNA, but it is present in a somato-dendritic distribution in output neurons of the cerebellum, cerebral cortex, and hippocampus, as well as in Purkinje cells in the cerebellar granule cell layer. Nav1.1, Nav1.2, Nav1.3, and Nav1.6 are present in neurons and glia, although the function of the channels in glial cells is not well understood. The isoforms in the CNS are present at different times in development, which has been studied most extensively in the rat. Nav1.1, Nav1.2, and Nav1.6 are present at significant levels in the adult CNS. Nav1.1 expression increases during the third postnatal week and peaks at the end of the first postnatal month, after which levels decrease by about 50% in the adult. Nav1.2 expression also increases during the third postnatal week, but then continues to increase until reaching maximal levels during adulthood. Nav1.6 is the most abundantly expressed isoform in the CNS during adulthood but it was detected during the embryonic period in brain, and levels increased shortly after birth and peaked by 2-weeks of age. Levels of Nav1.3 peak at birth but remain detectable at a lower level in adulthood.
Skeletal and Heart Muscle Channels 
Nav1.4 and Nav1.5 are expressed at significant levels in skeletal or cardiac muscle. Nav1.4 is expressed at high levels in adult skeletal muscle, at low levels in neonatal skeletal muscle, and not at all in brain or heart. Nav1.5 is present at high levels in heart, but not in liver, kidney, or uterus. Nav1.5 is not observed in adult skeletal muscle, but it is detectable in neonatal skeletal muscle and after denervation of adult muscle. Although both isoforms are present in denervated skeletal muscle, the increase in the level of sodium channel mRNA following denervation results from an induction of Nav1.5 expression.
Peripheral Nervous System Channels 
Nav1.7, Nav1.8, and Nav1.9 are expressed primarily in the PNS. The Nav1.1 isoform has been shown to be expressed at high levels in the PNS whereas the levels of Nav1.2 and Nav1.3 are significantly higher in the CNS than in the PNS. Nav1.6 is the most abundantly expressed channel in the CNS, and it can also be detected in both gray and white matter in the spinal cord and in all diameter cells in the DRG, including both motor and primary sensory neurons. This channel is also present at the nodes of Ranvier in the sciatic nerve, spinal cord, and optic nerve, locations at which the other isoforms were not detected. Nav1.7 is widespread in the PNS, present in all types of DRG neurons, in Schwann cells, and in neuroendocrine cells. The expression of Nav1.8 is more localized and found primarily in small diameter sensory neurons of the DRG and trigeminal ganglion, in which the channel has been observed during both neonatal and adult periods. The Nav1.9 channel is expressed in small fibers (sensory neurons) of the DRG and trigeminal ganglion, and the level of expression is down-regulated after axotomy.
The current density and gating properties of VGSC can also be modulated by the differential expression of channel “partners” or ChiPs:
For further information see Table 3 (VGSC protein partners) in 
Mutations in any of the genes encoding the alfa-subunits (SCN1A–SCN11A) and beta-subunits (SCN1B–SCN4B) can alter the structure of the channel and, thus, its biophysical properties leading to the development of “channelopathies”. Channelopathies are associated with autosomal dominant inheritance and de novo mutations and they can be classified in four groups depending on the predominant organ involved:
When the cell membrane is depolarized by a few millivolts, sodium channels activate and inactivate within milliseconds. Influx of sodium ions through the integral membrane proteins comprising the channel depolarizes the membrane further and initiates the rising phase of the action potential. 
There are significant differences among the three isoforms with respect to persistent current:
 HHNa (Model ID = 2)
 McCormick Na (Model ID = 34)
 Na (Model ID = 35)
 Na_S (Model ID = 36)
 NaP (Model ID = 37)
 Nap_Et2 (Model ID = 51)
 NaTa_t (Model ID = 52)
 NaTs2_t (Model ID = 53)
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Contributors : Rajnish Ranjan, Michael Schartner, Erika Borcel
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