View source for Sodium channel

{{Short description|Transmembrane protein allowing sodium ions in and out}}
[[File:Membrane Permeability of a Neuron During an Action Potential.svg|thumb|C is the sodium channel ]]
'''Sodium channels''' are [[integral membrane protein]]s that form [[ion channel]]s, conducting [[sodium ions]] (Na<sup>+</sup>) through a [[cell (biology)|cell's]] [[cell membrane|membrane]].<ref name="isbn0-8385-7701-6">{{cite book |author=Jessell TM, [[Eric R. Kandel|Kandel ER]], Schwartz JH |title=Principles of Neural Science |publisher=McGraw-Hill |location=New York |year=2000 |edition=4th |pages=[https://archive.org/details/isbn_9780838577011/page/154 154–69] |isbn=978-0-8385-7701-1 |url-access=registration |url=https://archive.org/details/isbn_9780838577011/page/154 }}</ref><ref name="isbn0-87893-321-2">{{cite book |author=[[Bertil Hille]]l |title=Ion Channels of Excitable Membranes |publisher=Sinauer |location=Sunderland, Mass |year=2001 |edition=3rd |pages=73–7 |isbn=978-0-87893-321-1 }}</ref> They belong to the [[Cation channel superfamily|superfamily of cation channels]].

==Classification==
They are classified into 2 types:
{| {{table}}
! Type of sodium channel !! Synonyms !! Trigger<br>(factor that stimulates the channel)
|-
|[[Voltage-gated sodium channels]]
|{{ubl|"VGSCs"|"voltage-dependent"|"voltage-sensitive"|"Nav channel"}}
|change in [[membrane potential]], which is also called change in voltage
|-
|[[ligand-gated sodium channels]]
|LGSCs
|binding of substances such as [[ligand]]s to the channel
|-
|Leak sodium channel
|NALCN
|Ungated, always open
|}

==Function==
In [[excitable cell]]s such as [[neuron]]s, [[muscle|myocytes]], and certain types of [[glia]], sodium channels are responsible for the [[Action potential#Stimulation and rising phase|rising phase]] of [[action potentials]]. These channels go through three different states called resting, active and inactive states. Even though the resting and inactive states would not allow the ions to flow through the channels the difference exists with respect to their structural conformation.

==Selectivity==
Sodium channels are highly selective for the transport of ions across cell membranes. The high selectivity with respect to the sodium ion is achieved in many different ways. All involve encapsulation of the sodium ion in a cavity of specific size within a larger molecule.<ref>{{cite book | first1 = Carmay | last1 = Lim | first2 = Todor | last2 = Dudev | name-list-style = vanc | publisher = Springer | date = 2016 | series = Metal Ions in Life Sciences | volume = 16 | title = The Alkali Metal Ions: Their Role in Life | editor1-last = Astrid | editor1-first = Sigel | editor2-last = Helmut | editor2-first = Sigel | editor3-last = Roland K.O. | editor3-first = Sigel | chapter = Chapter 10. Potassium Versus Sodium Selectivity in Monovalent Ion Channel Selectivity Filters | pages = 325–347 | doi = 10.1007/978-3-319-21756-7_9 | pmid = 26860305 | isbn = 978-3-319-21755-0 }}</ref>

==Voltage-gated sodium channels {{anchor|Voltage-gated}}==
{{Main|voltage-gated sodium channel}}

=== Structure ===
[[File:Sodium-channel.svg|thumb|640px|Diagram of a voltage-sensitive sodium channel α-subunit. G – [[glycosylation]], P – [[phosphorylation]], S – ion selectivity, I – inactivation. Positive (+) charges in S4 are important for transmembrane voltage sensing.<ref name=Yu>{{cite journal | vauthors = Yu FH, Catterall WA | title = Overview of the voltage-gated sodium channel family | journal = Genome Biology | volume = 4 | issue = 3 | pages = 207 | year = 2003 | pmid = 12620097 | pmc = 153452 | doi = 10.1186/gb-2003-4-3-207 | doi-access = free }}</ref>]]

Sodium channels consist of large [[Sodium channel#Alpha subunits|alpha subunits]] that associate with accessory proteins, such as [[Sodium channel#Beta subunits|beta subunits]]. An alpha subunit forms the core of the channel and is functional on its own. When the alpha subunit protein is expressed by a cell, it is able to form a pore in the cell membrane that conducts Na<sup>+</sup> in a voltage-dependent way, even if beta 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 alpha subunit consists of four repeat domains, labelled I through IV, each containing six membrane-spanning segments, labelled S1 through S6. The highly [[conservation (genetics)|conserved]] S4 segment acts as the channel's voltage sensor. The voltage sensitivity of this channel is due to positive amino acids located at every third position.<ref>Nicholls, Martin, Fuchs, Brown, Diamond, Weisblat. (2012) "From Neuron to Brain," 5th ed. pg. 86</ref> When stimulated by a change in [[transmembrane voltage]], this segment moves toward the extracellular side of the cell membrane, allowing the channel to become permeable to ions. The ions are conducted through the central pore cavity, which consists of two main 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 the pore gate and is formed by the combined S5 and S6 segments of the four domains. The pore domain also features lateral tunnels or fenestrations that run perpendicular to the pore axis. These fenestrations that connect the central cavity to the membrane are proposed to be important for drug accessibility.<ref>Hille, B. (1977) Local Anesthetics: Hydrophilic and Hydrophobic Pathways for the Drug-Receptor Reaction. The Journal of General Physiology, 69, 497-515.
http://dx.doi.org/10.1085/jgp.69.4.497</ref><ref>Gamal El-Din, Tamer M., et al. "Fenestrations control resting-state block of a voltage-gated sodium channel." Proceedings of the National Academy of Sciences 115.51 (2018): 13111-13116. https://doi.org/10.1073/pnas.1814928115</ref><ref>Tao, Elaine, and Ben Corry. "Characterizing fenestration size in sodium channel subtypes and their accessibility to inhibitors." Biophysical Journal 121.2 (2022): 193-206. https://doi.org/10.1016/j.bpj.2021.12.025</ref>

In mammalian sodium channels, the region linking domains III and IV is also important for channel function. This DIII-IV linker is responsible for wedging the pore gate shut after channel opening, inactivating it.<ref>Yan, Zhen, et al. "Structure of the Nav1. 4-β1 complex from electric eel." Cell 170.3 (2017): 470-482. https://doi.org/10.1016/j.cell.2017.06.039</ref>

===Gating===
Voltage-gated Na<sup>+</sup> channels have three main conformational states: closed, open and inactivated. Forward/back transitions between these states are correspondingly referred to as activation/deactivation (between open and closed, respectively), inactivation/reactivation (between inactivated and open, respectively), and recovery from inactivation/closed-state inactivation (between inactivated and closed, respectively). Closed and inactivated states are ion impermeable.

Before an action potential occurs, the axonal membrane is at its normal [[resting potential]], about −70 mV in most human neurons, and Na<sup>+</sup> channels are in their deactivated state, blocked on the extracellular side by their '''activation gates'''. In response to an increase of the membrane potential to about −55 mV (in this case, caused by an action potential), the activation gates open, allowing positively charged Na<sup>+</sup> ions to flow into the neuron through the channels, and causing the voltage across the neuronal membrane to increase to +30 mV in human neurons. Because the voltage across the membrane is initially negative, as its voltage increases ''to'' and ''past'' zero (from −70 mV at rest to a maximum of +30 mV), it is said to depolarize. This increase in voltage constitutes the rising phase of an action potential.

{| class="wikitable"
|-
! Action Potential !! Membrane Potential !! Target Potential !! Gate's Target State !! Neuron's Target State
|-
| Resting || −70 mV || −55 mV || Deactivated → Activated || Polarized
|-
| Rising || −55 mV || 0 mV || Activated || Polarized → Depolarized
|-
| Rising || 0 mV || +30 mV || Activated → Inactivated || Depolarized
|-
| Falling || +30 mV || 0 mV || Inactivated || Depolarized → Repolarized
|-
| Falling || 0 mV || −70 mV || Inactivated || Repolarized
|-
| Undershot || −70 mV || −75 mV || Inactivated → Deactivated || Repolarized → Hyperpolarized
|-
| Rebounding || −75 mV || −70 mV || Deactivated || Hyperpolarized → Polarized
|}

At the peak of the action potential, when enough Na<sup>+</sup> has entered the neuron and the membrane's potential has become high enough, the Na<sup>+</sup> channels inactivate themselves by closing their '''[[ball and chain inactivation|inactivation gates]]'''. The inactivation gate can be thought of as a "plug" tethered to domains III and IV of the channel's intracellular alpha subunit. Closure of the inactivation gate causes Na<sup>+</sup> flow through the channel to stop, which in turn causes the membrane potential to stop rising. The closing of the inactivation gate creates a refractory period within each individual Na<sup>+</sup> channel. This refractory period eliminates the possibility of an action potential moving in the opposite direction back towards the soma. With its inactivation gate closed, the channel is said to be inactivated. With the Na<sup>+</sup> channel no longer contributing to the membrane potential, the potential decreases back to its resting potential as the neuron repolarizes and subsequently hyperpolarizes itself, and this constitutes the falling phase of an action potential. The refractory period of each channel is therefore vital in propagating the action potential unidirectionally down an axon for proper communication between neurons.

When the membrane's voltage becomes low enough, the inactivation gate reopens and the activation gate closes in a process called '''deinactivation'''. With the activation gate closed and the inactivation gate open, the Na<sup>+</sup> channel is once again in its deactivated state, and is ready to participate in another action potential.

When any kind of ion channel does not inactivate itself, it is said to be persistently (or tonically) active. Some kinds of ion channels are naturally persistently active. However, genetic mutations that cause persistent activity in other channels can cause disease by creating excessive activity of certain kinds of neurons. Mutations that interfere with Na<sup>+</sup> channel inactivation can contribute to cardiovascular diseases or epileptic seizures by '''window currents''', which can cause muscle and/or nerve cells to become over-excited.

====Modeling the behavior of gates====
The temporal behavior of Na<sup>+</sup> channels can be modeled by a [[hidden Markov model|Markovian]] scheme or by the [[Hodgkin–Huxley model|Hodgkin–Huxley]]-type formalism. In the former scheme, each channel occupies a distinct [[Classical mechanics|state]] with [[differential equation]]s describing transitions between states; in the latter, the channels are treated as a [[Statistical population|population]] that are affected by three independent gating variables. Each of these variables can attain a value between 1 (fully permeant to ions) and 0 (fully non-permeant), the product of these variables yielding the percentage of conducting channels. The Hodgkin–Huxley model can be shown to be equivalent to a Markovian model.{{Explain|date=September 2021}}

===Impermeability to other ions===
The pore of sodium channels contains a [[Potassium channel#Selectivity filter|selectivity filter]] made of negatively charged [[amino acid]] residues, which attract the positive Na<sup>+</sup> 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 [[nanometer|nm]] wide, which is just large enough to allow a single Na<sup>+</sup> ion with a water [[molecule]] associated to pass through. The larger K<sup>+</sup> ion cannot fit through this area. Ions of different sizes also cannot interact as well with the negatively charged [[glutamate|glutamic acid]] residues that line the pore. {{citation needed|date=May 2018}}

===Diversity===
Voltage-gated sodium channels normally consist of an alpha subunit that forms the ion conduction pore and one to two beta subunits that have several functions including modulation of channel gating.<ref name=Isom>{{cite journal | vauthors = Isom LL | title = Sodium channel beta subunits: anything but auxiliary | journal = The Neuroscientist | volume = 7 | issue = 1 | pages = 42–54 | date = February 2001 | pmid = 11486343 | doi = 10.1177/107385840100700108 | s2cid = 86422657 }}</ref> Expression of the alpha subunit alone is sufficient to produce a functional channel.

====Alpha subunits====
[[Image:Sodium channel phylogram.png|thumb|right|'''Figure 1.''' Likely evolutionary relationship of the nine known human sodium channels.{{dubious|reason=Disagrees with IUPHAR image, is self-made by user Devon Ryan, and has a "this is wrong" comment from name-unknown on Commons page. Not great.|date=November 2023}}]]

The family of sodium channels has 9 known members, with amino acid identity >50% in the trans-membrane segments and extracellular loop regions. A standardized nomenclature for sodium channels is currently used and is maintained by the [[IUPHAR]].<ref name=Catterall>{{cite journal | vauthors = Catterall WA, Goldin AL, Waxman SG | title = International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 397–409 | date = December 2005 | pmid = 16382098 | doi = 10.1124/pr.57.4.4 | s2cid = 7332624 | url = https://semanticscholar.org/paper/2e6f7e97c54bc8cd20f0c9a6efb0deb6f5b5e20b }}</ref>

The proteins of these channels are named Na<sub>v</sub>1.1 through Na<sub>v</sub>1.9. The gene names are referred to as SCN1A through SCN5A, then SCN8A through SCN11A.<ref name=Catterall/> The "tenth member", Na<sub>x</sub>, does not act in a voltage-gated way. It has a loosely similar overall structure. Not much is known about its real function, other than that it also associates with beta subunits.<ref name="wetpore">{{cite journal |last1=Noland |first1=Cameron L. |last2=Chua |first2=Han Chow |last3=Kschonsak |first3=Marc |last4=Heusser |first4=Stephanie Andrea |last5=Braun |first5=Nina |last6=Chang |first6=Timothy |last7=Tam |first7=Christine |last8=Tang |first8=Jia |last9=Arthur |first9=Christopher P. |last10=Ciferri |first10=Claudio |last11=Pless |first11=Stephan Alexander |last12=Payandeh |first12=Jian |title=Structure-guided unlocking of NaX reveals a non-selective tetrodotoxin-sensitive cation channel |journal=Nature Communications |date=17 March 2022 |volume=13 |issue=1 |page=1416 |doi=10.1038/s41467-022-28984-4|pmid=35301303 |pmc=8931054 }}</ref>

The probable evolutionary relationship between these channels, based on the similarity of their amino acid sequences, is shown in figure 1.  The individual sodium channels are distinguished not only by differences in their sequence but also by their kinetics and expression profiles. Some of this data is summarized in table 1, below.
{{clear}}

{| class="wikitable" style="text-align:center"
|+ '''Table 1.''' Nomenclature and some functions of voltage-gated sodium channel alpha subunits
|-
! Protein name !! Gene !! Expression profile !! Associated human [[Channelopathy|channelopathies]]
|-
! [[Nav1.1|Na<sub>v</sub>1.1]]
| {{Gene|SCN1A}} || [[Central nervous system|Central neurons]], [peripheral neurons] and [[cardiac myocytes]] || febrile [[epilepsy]], [[generalized epilepsy with febrile seizures plus|GEFS+]], [[Dravet syndrome]] (also known as ''severe myclonic epilepsy of infancy'' or SMEI), borderline SMEI (SMEB), West syndrome (also known as ''infantile spasms''), Doose syndrome (also known as ''myoclonic astatic epilepsy''), intractable childhood epilepsy with generalized tonic-clonic seizures (ICEGTC), Panayiotopoulos syndrome, familial hemiplegic migraine (FHM), familial autism, Rasmussens's encephalitis and Lennox-Gastaut syndrome<ref name="urlwww.scn1a.info - SCN1A infobase">{{cite web | url = http://www.scn1a.info/ | title = SCN1A infobase | author = Lossin C | archive-date = 2011-07-21 | quote = compilation of genetic variations in the SCN1A gene that alter the expression or function of Nav1.1 | access-date = 2009-10-30 | url-status = live | archive-url = https://web.archive.org/web/20110721232702/http://www.scn1a.info/ }}</ref>
|-
! [[Nav1.2|Na<sub>v</sub>1.2]]
| {{Gene|SCN2A}} || Central neurons, peripheral neurons || inherited [[febrile seizure]]s, [[epilepsy]], and [[autism spectrum disorder]] 
|-
! [[SCN3A|Na<sub>v</sub>1.3]]
| {{Gene|SCN3A}} || Central neurons, peripheral neurons and cardiac myocytes || epilepsy, pain, brain malformations<ref name=":1">{{cite journal | vauthors = Bennett DL, Clark AJ, Huang J, Waxman SG, Dib-Hajj SD | title = The Role of Voltage-Gated Sodium Channels in Pain Signaling | journal = Physiological Reviews | volume = 99 | issue = 2 | pages = 1079–1151 | date = April 2019 | pmid = 30672368 | doi = 10.1152/physrev.00052.2017 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Smith RS, Kenny CJ, Ganesh V, Jang A, Borges-Monroy R, Partlow JN, Hill RS, Shin T, Chen AY, Doan RN, Anttonen AK, Ignatius J, Medne L, Bönnemann CG, Hecht JL, Salonen O, Barkovich AJ, Poduri A, Wilke M, de Wit MC, Mancini GM, Sztriha L, Im K, Amrom D, Andermann E, Paetau R, Lehesjoki AE, Walsh CA, Lehtinen MK | display-authors = 6 | title = V1.3) Regulation of Human Cerebral Cortical Folding and Oral Motor Development | journal = Neuron | volume = 99 | issue = 5 | pages = 905–913.e7 | date = September 2018 | pmid = 30146301 | doi = 10.1016/j.neuron.2018.07.052 | pmc = 6226006 | doi-access = free }}</ref>
|-
! [[Nav1.4|Na<sub>v</sub>1.4]]
| {{Gene|SCN4A}} || [[Skeletal muscle]] || [[hyperkalemic periodic paralysis]], [[paramyotonia congenita]], and [[potassium-aggravated myotonia]]
|-
! [[Nav1.5|Na<sub>v</sub>1.5]]
| {{Gene|SCN5A}} || Cardiac myocytes, uninnervated skeletal muscle, central neurons, gastrointestinal smooth muscle cells and Interstitial cells of Cajal || Cardiac: [[Long QT syndrome]] Type 3, [[Brugada syndrome]], [[Lev's disease|progressive cardiac conduction disease]], familial [[atrial fibrillation]] and idiopathic [[ventricular fibrillation]];<ref>{{cite journal | vauthors = Chockalingam P, Wilde A | title = The multifaceted cardiac sodium channel and its clinical implications | journal = Heart | volume = 98 | issue = 17 | pages = 1318–24 | date = September 2012 | pmid = 22875823 | doi = 10.1136/heartjnl-2012-301784 | s2cid = 44433455 }}</ref>
Gastrointestinal: [[Irritable bowel syndrome]];<ref name="pmid24613995">{{cite journal | vauthors = Beyder A, Mazzone A, Strege PR, Tester DJ, Saito YA, Bernard CE, Enders FT, Ek WE, Schmidt PT, Dlugosz A, Lindberg G, Karling P, Ohlsson B, Gazouli M, Nardone G, Cuomo R, Usai-Satta P, Galeazzi F, Neri M, Portincasa P, Bellini M, Barbara G, Camilleri M, Locke GR, Talley NJ, D'Amato M, Ackerman MJ, Farrugia G | title = Loss-of-function of the voltage-gated sodium channel NaV1.5 (channelopathies) in patients with irritable bowel syndrome | journal = Gastroenterology | volume = 146 | issue = 7 | pages = 1659–1668 | date = June 2014 | pmid = 24613995 | pmc = 4096335 | doi = 10.1053/j.gastro.2014.02.054 }}</ref>
|-
! [[SCN8A|Na<sub>v</sub>1.6]]
| {{Gene|SCN8A}} || Central neurons, [[dorsal root ganglia]], [[peripheral nervous system|peripheral neurons]], heart, glia cells || [[Epilepsy]],<ref>{{cite journal | vauthors = Butler KM, da Silva C, Shafir Y, Weisfeld-Adams JD, Alexander JJ, Hegde M, Escayg A | title = De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis | journal = Epilepsy Research | volume = 129 | pages = 17–25 | date = January 2017 | pmid = 27875746 | pmc = 5321682 | doi = 10.1016/j.eplepsyres.2016.11.002 }}</ref>  [[ataxia]], [[dystonia]], [[tremor]]<ref>{{cite journal | vauthors = Meisler MH, Kearney JA | title = Sodium channel mutations in epilepsy and other neurological disorders | journal = The Journal of Clinical Investigation | volume = 115 | issue = 8 | pages = 2010–7 | date = August 2005 | pmid = 16075041 | pmc = 1180547 | doi = 10.1172/JCI25466 | url = }}</ref>
|-
! [[Nav1.7|Na<sub>v</sub>1.7]]
| {{Gene|SCN9A}} || [[Dorsal root ganglia]], sympathetic neurons, [[Schwann cells]], and [[neuroendocrine cells]] || [[erythromelalgia]], [[paroxysmal extreme pain disorder|PEPD]], [[congenital insensitivity to pain|channelopathy-associated insensitivity to pain]]<ref name=":1" /> and recently discovered a disabling form of [[fibromyalgia]] (rs6754031 polymorphism)<ref name="pmid22348792">{{cite journal | vauthors = Vargas-Alarcon G, Alvarez-Leon E, Fragoso JM, Vargas A, Martinez A, Vallejo M, Martinez-Lavin M | title = A SCN9A gene-encoded dorsal root ganglia sodium channel polymorphism associated with severe fibromyalgia | journal = BMC Musculoskeletal Disorders | volume = 13 | pages = 23 | date = February 2012 | pmid = 22348792 | pmc = 3310736 | doi = 10.1186/1471-2474-13-23 | doi-access = free }}</ref>
|-
! [[Nav1.8|Na<sub>v</sub>1.8]]
| {{Gene|SCN10A}} || Dorsal root ganglia || pain,<ref name=":1" /> neuropsychiatric disorders
|-
! [[Nav1.9|Na<sub>v</sub>1.9]]
| {{Gene|SCN11A}} || Dorsal root ganglia || pain<ref name=":1" />
|-
! [[SCN7A|Na<sub>x</sub>]]
| {{Gene|SCN7A}} || heart, uterus, skeletal muscle, astrocytes, dorsal root ganglion cells || none known
|}

====Beta subunits====
Sodium channel beta subunits are type 1 transmembrane glycoproteins with an extracellular N-terminus and a cytoplasmic C-terminus. As members of the Ig superfamily, beta subunits contain a prototypic V-set Ig loop in their extracellular domain. They do not share any homology with their counterparts of calcium and potassium channels.<ref name="pmid10798388">{{cite journal | vauthors = Catterall WA | title = From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels | journal = Neuron | volume = 26 | issue = 1 | pages = 13–25 | date = April 2000 | pmid = 10798388 | doi = 10.1016/S0896-6273(00)81133-2 | s2cid = 17928749 | doi-access = free }}</ref> Instead, they are homologous to neural cell adhesion molecules (CAMs) and the large family of L1 CAMs. There are four distinct betas named in order of discovery: SCN1B, SCN2B, SCN3B, SCN4B (table 2). Beta 1 and beta 3 interact with the alpha subunit non-covalently, whereas beta 2 and beta 4 associate with alpha via disulfide bond.<ref name="pmid1375395">{{cite journal | vauthors = Isom LL, De Jongh KS, Patton DE, Reber BF, Offord J, Charbonneau H, Walsh K, Goldin AL, Catterall WA | title = Primary structure and functional expression of the beta 1 subunit of the rat brain sodium channel | journal = Science | volume = 256 | issue = 5058 | pages = 839–42 | date = May 1992 | pmid = 1375395 | doi = 10.1126/science.1375395 | bibcode = 1992Sci...256..839I }}</ref> Sodium channels are more likely to stay open at the subthreshold membrane potential when interacting with beta toxins, which in turn induces an immediate sensation of pain.<ref>{{Cite web|url=https://blackboard.jhu.edu/courses/1/AS.410.603.83.SU20/db/_10095565_1/Isolation%20and%20Characterization%20of%20CvIV4%20A%20Pain%20Inducing%20a-scorpion%20Toxin.pdf|access-date=2020-07-16|website=blackboard.jhu.edu|title=Blackboard Server Unavailable }}</ref>

====Role of beta subunits as cell adhesion molecules====
In addition to regulating channel gating, sodium channel beta subunits also modulate channel expression and form links to the [[intracellular]] [[cytoskeleton]] via [[ankyrin]] and [[spectrin]].<ref name="Isom" /><ref name="pmid10753953">{{cite journal | vauthors = Malhotra JD, Kazen-Gillespie K, Hortsch M, Isom LL | title = Sodium channel beta subunits mediate homophilic cell adhesion and recruit ankyrin to points of cell-cell contact | journal = The Journal of Biological Chemistry | volume = 275 | issue = 15 | pages = 11383–8 | date = April 2000 | pmid = 10753953 | doi = 10.1074/jbc.275.15.11383 | doi-access =  free}}</ref><ref name="pmid11997395">{{cite journal | vauthors = Malhotra JD, Koopmann MC, Kazen-Gillespie KA, Fettman N, Hortsch M, Isom LL | title = Structural requirements for interaction of sodium channel beta 1 subunits with ankyrin | journal = The Journal of Biological Chemistry | volume = 277 | issue = 29 | pages = 26681–8 | date = July 2002 | pmid = 11997395 | doi = 10.1074/jbc.M202354200 | doi-access = free }}</ref>
Voltage-gated sodium channels also assemble with a variety of other proteins, such as FHF proteins (Fibroblast growth factor Homologous Factor), calmodulin, cytoskeleton or regulatory kinases,<ref name="pmid11389473">{{cite journal | vauthors = Cantrell AR, Catterall WA | title = Neuromodulation of Na+ channels: an unexpected form of cellular plasticity | journal = Nature Reviews. Neuroscience | volume = 2 | issue = 6 | pages = 397–407 | date = June 2001 | pmid = 11389473 | doi = 10.1038/35077553 | s2cid = 22885909 }}</ref><ref name="Isom" /><ref name="pmid15317864">{{cite journal | vauthors = Shah BS, Rush AM, Liu S, Tyrrell L, Black JA, Dib-Hajj SD, Waxman SG | title = Contactin associates with sodium channel Nav1.3 in native tissues and increases channel density at the cell surface | journal = The Journal of Neuroscience | volume = 24 | issue = 33 | pages = 7387–99 | date = August 2004 | pmid = 15317864 | pmc = 6729770 | doi = 10.1523/JNEUROSCI.0322-04.2004 }}</ref><ref name="pmid15282281">{{cite journal | vauthors = Wittmack EK, Rush AM, Craner MJ, Goldfarb M, Waxman SG, Dib-Hajj SD | title = Fibroblast growth factor homologous factor 2B: association with Nav1.6 and selective colocalization at nodes of Ranvier of dorsal root axons | journal = The Journal of Neuroscience | volume = 24 | issue = 30 | pages = 6765–75 | date = July 2004 | pmid = 15282281 | pmc = 6729706 | doi = 10.1523/JNEUROSCI.1628-04.2004 }}</ref><ref name="pmid16817858">{{cite journal | vauthors = Rush AM, Wittmack EK, Tyrrell L, Black JA, Dib-Hajj SD, Waxman SG | title = Differential modulation of sodium channel Na(v)1.6 by two members of the fibroblast growth factor homologous factor 2 subfamily | journal = The European Journal of Neuroscience | volume = 23 | issue = 10 | pages = 2551–62 | date = May 2006 | pmid = 16817858 | doi = 10.1111/j.1460-9568.2006.04789.x | s2cid = 21411801 }}</ref> which form a complex with sodium channels, influencing its expression and/or function.  Several beta subunits interact with one or more [[extracellular matrix]] (ECM) molecules. Contactin, also known as F3 or F11, associates with beta 1 as shown via co-immunoprecipitation.<ref name="pmid11567041">{{cite journal | vauthors = Kazarinova-Noyes K, Malhotra JD, McEwen DP, Mattei LN, Berglund EO, Ranscht B, Levinson SR, Schachner M, Shrager P, Isom LL, Xiao ZC | title = Contactin associates with Na+ channels and increases their functional expression | journal = The Journal of Neuroscience | volume = 21 | issue = 19 | pages = 7517–25 | date = October 2001 | pmid = 11567041 | pmc = 6762905 | doi =  10.1523/JNEUROSCI.21-19-07517.2001}}</ref> [[Fibronectin]]-like (FN-like) repeats of [[Tenascin]]-C and [[Tenascin]]-R bind with beta 2 in contrast to the [[Epidermal growth factor]]-like (EGF-like) repeats that repel beta2.<ref name="pmid9861042">{{cite journal | vauthors = Srinivasan J, Schachner M, Catterall WA | title = Interaction of voltage-gated sodium channels with the extracellular matrix molecules tenascin-C and tenascin-R | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 26 | pages = 15753–7 | date = December 1998 | pmid = 9861042 | pmc = 28116 | doi = 10.1073/pnas.95.26.15753 | bibcode = 1998PNAS...9515753S | doi-access = free }}</ref> A disintegrin and metalloproteinase (ADAM) 10 sheds beta 2's [[ectodomain]] possibly inducing neurite outgrowth.<ref name="pmid15833746">{{cite journal | vauthors = Kim DY, Ingano LA, Carey BW, Pettingell WH, Kovacs DM | title = Presenilin/gamma-secretase-mediated cleavage of the voltage-gated sodium channel beta2-subunit regulates cell adhesion and migration | journal = The Journal of Biological Chemistry | volume = 280 | issue = 24 | pages = 23251–61 | date = June 2005 | pmid = 15833746 | doi = 10.1074/jbc.M412938200 | doi-access = free }}</ref>  Beta 3 and beta 1 bind to neurofascin at Nodes of Ranvier in developing neurons.<ref name="pmid11470829">{{cite journal | vauthors = Ratcliffe CF, Westenbroek RE, Curtis R, Catterall WA | title = Sodium channel beta1 and beta3 subunits associate with neurofascin through their extracellular immunoglobulin-like domain | journal = The Journal of Cell Biology | volume = 154 | issue = 2 | pages = 427–34 | date = July 2001 | pmid = 11470829 | pmc = 2150779 | doi = 10.1083/jcb.200102086 }}</ref>

{| class="wikitable" style="text-align:center"
|+ '''Table 2.''' Nomenclature and some functions of voltage-gated sodium channel beta subunits
|-
! '''Protein name''' !! '''Gene link''' !! Assembles with  !!  Expression profile !! Associated human [[Channelopathy|channelopathies]]
|- 
| [[SCN1B|Na<sub>v</sub>β1]] || {{Gene|SCN1B}} || Na<sub>v</sub>1.1 to Na<sub>v</sub>1.7 || Central Neurons, Peripheral Neurons, skeletal muscle, heart, glia || epilepsy (GEFS+), [[Brugada syndrome]]<ref name=":0">{{cite journal | vauthors = Antzelevitch C, Patocskai B | title = Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects | journal = Current Problems in Cardiology | volume = 41 | issue = 1 | pages = 7–57 | date = January 2016 | pmid = 26671757 | pmc = 4737702 | doi = 10.1016/j.cpcardiol.2015.06.002 }}</ref>
|- 
| [[SCN2B|Na<sub>v</sub>β2]] || {{Gene|SCN2B}} || Na<sub>v</sub>1.1, Na<sub>v</sub>1.2, Na<sub>v</sub>1.5 to Na<sub>v</sub>1.7 || Central Neurons, peripheral neurons, heart, glia ||[[Brugada syndrome]]<ref name=":0" />
|- 
| [[SCN3B|Na<sub>v</sub>β3]] || {{Gene|SCN3B}} || Na<sub>v</sub>1.1 to Na<sub>v</sub>1.3, Na<sub>v</sub>1.5 || central neurons, adrenal gland, kidney, peripheral neurons ||[[Brugada syndrome]]<ref name=":0" />
|- 
| [[SCN4B|Na<sub>v</sub>β4]] || {{Gene|SCN4B}} || Na<sub>v</sub>1.1, Na<sub>v</sub>1.2, Na<sub>v</sub>1.5 || heart, skeletal muscle, central and peripheral neurons || none known
|}

==Ligand-gated sodium channels {{anchor|Ligand-gated}}==
[[Ligand-gated]] sodium channels are activated by binding of a [[Ligand (biochemistry)|ligand]] instead of a change in membrane potential.

They are found, e.g. in the [[neuromuscular junction]] as [[nicotinic receptors]], where the ligands are [[acetylcholine]] molecules. Most channels of this type are permeable to potassium to some degree as well as to sodium.

==Role in action potential==
{{main|Action potential}}
Voltage-gated sodium channels play an important role in [[action potential]]s. If enough channels open when there is a change in the cell's [[membrane potential]], a small but significant number of Na<sup>+</sup> ions will move into the cell down their [[electrochemical gradient]], further [[depolarization|depolarizing]] the cell. Thus, the more Na<sup>+</sup> channels localized in a region of a cell's membrane the faster the action potential will propagate and the more '''excitable''' that area of the cell will be. This is an example of a [[positive feedback loop]]. The ability of these channels to assume a closed-inactivated state causes the [[refractory period (physiology)|refractory period]] and is critical for the propagation of action potentials down an [[axon]].

Na<sup>+</sup> channels both open and close more quickly than [[potassium channel|K<sup>+</sup> channels]], producing an influx of positive charge (Na<sup>+</sup>) toward the beginning of the [[action potential]] and an efflux (K<sup>+</sup>) toward the end.

Ligand-gated sodium channels, on the other hand, create the change in the membrane potential in the first place, in response to the binding of a ligand to it. Leak sodium channels additionally contribute to action potential regulation by modulating the resting potential (and in turn, the excitability) of a cell.<ref name=":2">{{Cite journal |last=Ren |first=Dejian |date=2011-12-22 |title=Sodium leak channels in neuronal excitability and rhythmic behaviors |journal=Neuron |volume=72 |issue=6 |pages=899–911 |doi=10.1016/j.neuron.2011.12.007 |issn=1097-4199 |pmc=3247702 |pmid=22196327}}</ref>

==Pharmacologic modulation==

===Blockers===
{{main|Sodium channel blocker}}

===Activators===
{{See also|Sodium channel opener}}
The following naturally produced substances persistently activate (open) sodium channels:

* [[Alkaloid]]-based toxins
** [[aconitine]]
** [[batrachotoxin]]
** [[brevetoxin]]
** [[ciguatoxin]]
** [[delphinine]]
** some [[grayanotoxins]], e.g., grayanotoxin I (other granotoxins inactive, or close, sodium channels)
** [[veratridine]]

===Gating modifiers===
The following toxins modify the gating of sodium channels:

* [[Peptide]]-based toxins
** [[μ-Conotoxin]]
** [[δ-Atracotoxin]]<ref name=Grolleau_2000>{{cite journal | vauthors = Grolleau F, Stankiewicz M, Birinyi-Strachan L, Wang XH, Nicholson GM, Pelhate M, Lapied B | title = Electrophysiological analysis of the neurotoxic action of a funnel-web spider toxin, delta-atracotoxin-HV1a, on insect voltage-gated Na+ channels | journal = The Journal of Experimental Biology | volume = 204 | issue = Pt 4 | pages = 711–21 | date = February 2001 | doi = 10.1242/jeb.204.4.711 | pmid = 11171353 | hdl = 10453/5728 | hdl-access = free }}</ref>
** [[Scorpion venom]] toxins<ref name="pmid10491073">{{cite journal | vauthors = Possani LD, Becerril B, Delepierre M, Tytgat J | title = Scorpion toxins specific for Na+-channels | journal = European Journal of Biochemistry | volume = 264 | issue = 2 | pages = 287–300 | date = September 1999 | pmid = 10491073 | doi = 10.1046/j.1432-1327.1999.00625.x | doi-access = free }}</ref>

== Sodium leak channel (NALCN) ==
Sodium leak channels do not show any voltage or ligand gating. Instead, they are always open or "leaking" a small background current to regulate the resting membrane potential of a neuron.<ref name=":2" /> In most animals, a single gene encodes the NALCN (sodium leak channel, nonselective) protein.<ref name=":3">{{Cite journal |last1=Lee |first1=Jung-Ha |last2=Cribbs |first2=Leanne L. |last3=Perez-Reyes |first3=Edward |date=1999-02-26 |title=Cloning of a novel four repeat protein related to voltage-gated sodium and calcium channels |url=https://febs.onlinelibrary.wiley.com/doi/10.1016/S0014-5793%2899%2900082-4 |journal=FEBS Letters |language=en |volume=445 |issue=2–3 |pages=231–236 |doi=10.1016/S0014-5793(99)00082-4 |pmid=10094463 |s2cid=26183219 |issn=0014-5793}}</ref>

=== Structural and functional differences ===
Despite following the same basic structure as other sodium channels, NALCN is not sensitive to voltage changes. The voltage-sensitive S4 transmembrane domain of NALCN has fewer positively charged amino acids (13 instead of a voltage gated channel's 21) possibly explaining its voltage insensitivity.<ref name=":2" /> NALCN is also far less selective for Na<sup>+</sup> ions and is permeable to Ca<sup>2+</sup> and K<sup>+</sup> ions. The EEKE amino acid motif in the pore filter domain of NALCN is similar to both the EEEE motif of [[voltage-gated calcium channel]] and the DEKA motif of the voltage-gated sodium channel, possibly explaining its lack of selectivity.<ref name=":3" />
[[File:NALCN activity.png|thumb|392x392px|Regulatory pathways and chemicals affecting NALCN function.]]
NALCN is not blocked by many common sodium channel blockers, including [[tetrodotoxin]]. NALCN is blocked nonspecifically by both Gd<sup>3+</sup> and [[verapamil]].<ref name=":9">{{Cite journal |last1=Lu |first1=Boxun |last2=Su |first2=Yanhua |last3=Das |first3=Sudipto |last4=Liu |first4=Jin |last5=Xia |first5=Jingsheng |last6=Ren |first6=Dejian |date=2007-04-20 |title=The Neuronal Channel NALCN Contributes Resting Sodium Permeability and Is Required for Normal Respiratory Rhythm |journal=Cell |volume=129 |issue=2 |pages=371–383 |doi=10.1016/j.cell.2007.02.041 |s2cid=17165089 |issn=0092-8674|doi-access=free |pmid=17448995 }}</ref> [[Substance P]] and [[neurotensin]] both activate [[Src family kinase]]s through their respective [[G protein-coupled receptor|GPCRs]] (independent of the coupled [[G protein|G-proteins]]) which in turn increase the permeability of NALCN through UNC80 activation.<ref name=":4">{{Cite journal |last1=Lu |first1=Boxun |last2=Su |first2=Yanhua |last3=Das |first3=Sudipto |last4=Wang |first4=Haikun |last5=Wang |first5=Yan |last6=Liu |first6=Jin |last7=Ren |first7=Dejian |date=2009-02-05 |title=Peptide neurotransmitters activate a cation channel complex of NALCN and UNC-80 |journal=Nature |volume=457 |issue=7230 |pages=741–744 |doi=10.1038/nature07579 |issn=1476-4687 |pmc=2810458 |pmid=19092807|bibcode=2009Natur.457..741L }}</ref> [[Acetylcholine]] can also increase NALCN activity through [[Muscarinic acetylcholine receptor M3|M<sub>3</sub> muscarinic acetylcholine receptors]].<ref name=":5">{{Cite journal |last1=Swayne |first1=Leigh Anne |last2=Mezghrani |first2=Alexandre |last3=Varrault |first3=Annie |last4=Chemin |first4=Jean |last5=Bertrand |first5=Gyslaine |last6=Dalle |first6=Stephane |last7=Bourinet |first7=Emmanuel |last8=Lory |first8=Philippe |last9=Miller |first9=Richard J. |last10=Nargeot |first10=Joel |last11=Monteil |first11=Arnaud |date=2009-07-03 |title=The NALCN ion channel is activated by M3 muscarinic receptors in a pancreatic beta-cell line |journal=EMBO Reports |volume=10 |issue=8 |pages=873–880 |doi=10.1038/embor.2009.125 |issn=1469-3178 |pmc=2710536 |pmid=19575010}}</ref> Higher levels of extracellular Ca<sup>2+</sup> decrease the permeability of NALCN by activating [[Calcium-sensing receptor|CaSR]] which inhibits UNC80.<ref name=":6">{{Cite journal |last1=Lu |first1=Boxun |last2=Zhang |first2=Qi |last3=Wang |first3=Haikun |last4=Wang |first4=Yan |last5=Nakayama |first5=Manabu |last6=Ren |first6=Dejian |date=2010-11-04 |title=Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex |journal=Neuron |volume=68 |issue=3 |pages=488–499 |doi=10.1016/j.neuron.2010.09.014 |issn=1097-4199 |pmc=2987630 |pmid=21040849}}</ref>

==== Protein Complex ====
NALCN complexes with the proteins UNC79, UNC80, and FAM155A.<ref>{{Cite journal |last1=Yeh |first1=Edward |last2=Ng |first2=Sharon |last3=Zhang |first3=Mi |last4=Bouhours |first4=Magali |last5=Wang |first5=Ying |last6=Wang |first6=Min |last7=Hung |first7=Wesley |last8=Aoyagi |first8=Kyota |last9=Melnik-Martinez |first9=Katya |last10=Li |first10=Michelle |last11=Liu |first11=Fang |last12=Schafer |first12=William R. |last13=Zhen |first13=Mei |date=2008-03-11 |title=A putative cation channel, NCA-1, and a novel protein, UNC-80, transmit neuronal activity in C. elegans |journal=PLOS Biology |volume=6 |issue=3 |pages=e55 |doi=10.1371/journal.pbio.0060055 |issn=1545-7885 |pmc=2265767 |pmid=18336069 |doi-access=free }}</ref><ref name=":7">{{Cite journal |last1=Humphrey |first1=John A. |last2=Hamming |first2=Kevin S. |last3=Thacker |first3=Colin M. |last4=Scott |first4=Robert L. |last5=Sedensky |first5=Margaret M. |last6=Snutch |first6=Terrance P. |last7=Morgan |first7=Phil G. |last8=Nash |first8=Howard A. |date=2007-04-03 |title=A Putative Cation Channel and Its Novel Regulator: Cross-Species Conservation of Effects on General Anesthesia |journal=Current Biology |volume=17 |issue=7 |pages=624–629 |doi=10.1016/j.cub.2007.02.037 |pmid=17350263 |s2cid=9395896 |issn=0960-9822|doi-access=free }}</ref><ref name=":8">{{Cite journal |last1=Xie |first1=Jiongfang |last2=Ke |first2=Meng |last3=Xu |first3=Lizhen |last4=Lin |first4=Shiyi |last5=Huang |first5=Jin |last6=Zhang |first6=Jiabei |last7=Yang |first7=Fan |last8=Wu |first8=Jianping |last9=Yan |first9=Zhen |date=2020-11-17 |title=Structure of the human sodium leak channel NALCN in complex with FAM155A |journal=Nature Communications |volume=11 |issue=1 |pages=5831 |doi=10.1038/s41467-020-19667-z |issn=2041-1723 |pmc=7672056 |pmid=33203861|bibcode=2020NatCo..11.5831X }}</ref> UNC79 appears to be linked to membrane stability of NALCN and linkage with UNC 80.<ref name=":7" /> UNC80 mediates chemical modulation of NALCN through multiple pathways.<ref name=":2" /><ref name=":6" /><ref name=":5" /><ref name=":4" /> FAM155A helps protein folding in the endoplasmic reticulum, chaperones transport to the axon, and contributes to membrane stability.<ref name=":8" />

=== Biological function ===
The [[Resting potential|resting membrane potential]] of a neuron is usually -60mV to -80mV, driven primarily by the K<sup>+</sup> potential at -90mV. The depolarization from the K<sup>+</sup> potential is due primarily to a small Na<sup>+</sup> leak current. About 70% of this current is through NALCN.<ref name=":9" /> Increasing NALCN permeability lowers the resting membrane potential, bringing it closer to the trigger of an action potential (-55mV), thus increasing the excitability of a neuron.

=== Role in pathology ===
Mutations to NALCN lead to severe disruptions to respiratory rhythm in mice<ref name=":9" /> and altered circadian locomotion in flies.<ref>{{Cite journal |last1=Lear |first1=Bridget C. |last2=Lin |first2=Jui-Ming |last3=Keath |first3=J. Russel |last4=McGill |first4=Jermaine J. |last5=Raman |first5=Indira M. |last6=Allada |first6=Ravi |date=2005-12-02 |title=The Ion Channel Narrow Abdomen Is Critical for Neural Output of the Drosophila Circadian Pacemaker |journal=Neuron |volume=48 |issue=6 |pages=965–976 |doi=10.1016/j.neuron.2005.10.030 |pmid=16364900 |s2cid=14910947 |issn=0896-6273|doi-access=free }}</ref> Mutations to NALCN have also been linked to multiple severe developmental disorders<ref>{{Cite journal |last1=Al-Sayed |first1=Moeenaldeen D. |last2=Al-Zaidan |first2=Hamad |last3=Albakheet |first3=Albandary |last4=Hakami |first4=Hana |last5=Kenana |first5=Rosan |last6=Al-Yafee |first6=Yusra |last7=Al-Dosary |first7=Mazhor |last8=Qari |first8=Alya |last9=Al-Sheddi |first9=Tarfa |last10=Al-Muheiza |first10=Muhammed |last11=Al-Qubbaj |first11=Wafa |last12=Lakmache |first12=Yamina |last13=Al-Hindi |first13=Hindi |last14=Ghaziuddin |first14=Muhammad |last15=Colak |first15=Dilek |date=2013-10-03 |title=Mutations in NALCN cause an autosomal-recessive syndrome with severe hypotonia, speech impairment, and cognitive delay |journal=American Journal of Human Genetics |volume=93 |issue=4 |pages=721–726 |doi=10.1016/j.ajhg.2013.08.001 |issn=1537-6605 |pmc=3791267 |pmid=24075186}}</ref> and cervical dystonia.<ref>{{Cite journal |last1=Mok |first1=Kin Y. |last2=Schneider |first2=Susanne A. |last3=Trabzuni |first3=Daniah |last4=Stamelou |first4=Maria |last5=Edwards |first5=Mark |last6=Kasperaviciute |first6=Dalia |last7=Pickering-Brown |first7=Stuart |last8=Silverdale |first8=Monty |last9=Hardy |first9=John |last10=Bhatia |first10=Kailash P. |date=2014-02-01 |title=Genomewide association study in cervical dystonia demonstrates possible association with sodium leak channel |journal=Movement Disorders|volume=29 |issue=2 |pages=245–251 |doi=10.1002/mds.25732 |issn=1531-8257 |pmc=4208301 |pmid=24227479}}</ref> Schizophrenia and bipolar disorder are also linked to mutations to NALCN.<ref>{{Cite journal |last1=Wang |first1=Ke-Sheng |last2=Liu |first2=Xue-Feng |last3=Aragam |first3=Nagesh |date=2010-12-01 |title=A genome-wide meta-analysis identifies novel loci associated with schizophrenia and bipolar disorder |url=https://www.sciencedirect.com/science/article/pii/S0920996410015318 |journal=Schizophrenia Research |volume=124 |issue=1 |pages=192–199 |doi=10.1016/j.schres.2010.09.002 |pmid=20889312 |s2cid=21402201 |issn=0920-9964}}</ref>

==pH modulation==
Changes in blood and tissue pH accompany physiological and pathophysiological conditions such as exercise, cardiac ischemia, ischemic stroke, and cocaine ingestion. These conditions are known to trigger the symptoms of electrical diseases in patients carrying sodium channel mutations. Protons cause a diverse set of changes to sodium channel gating, which generally lead to decreases in the amplitude of the transient sodium current and increases in the fraction of non-inactivating channels that pass persistent currents. These effects are shared with disease-causing mutants in neuronal, skeletal muscle, and cardiac tissue and may be compounded in mutants that impart greater proton sensitivity to sodium channels, suggesting a role of protons in triggering acute symptoms of electrical disease.<ref name=pmid29460150>{{cite book | vauthors = Peters CH, Ghovanloo MR, Gershome C, Ruben PC | chapter = pH Modulation of Voltage-Gated Sodium Channels | volume = 246 | pages = 147–160 | date = February 2018 | pmid = 29460150 | doi = 10.1007/164_2018_99 | series = Handbook of Experimental Pharmacology | isbn = 978-3-319-90283-8 | title = Voltage-gated Sodium Channels: Structure, Function and Channelopathies }}</ref>

===Molecular mechanisms of proton block===
Single channel data from cardiomyocytes have shown that protons can decrease the conductance of individual sodium channels.<ref name=pmid1664454>{{cite journal | vauthors = Zhang JF, Siegelbaum SA | title = Effects of external protons on single cardiac sodium channels from guinea pig ventricular myocytes | journal = The Journal of General Physiology | volume = 98 | issue = 6 | pages = 1065–83 | date = December 1991 | pmid = 1664454 | pmc = 2229074 | doi = 10.1085/jgp.98.6.1065 }}</ref> The sodium channel selectivity filter is composed of a single residue in each of the four pore-loops of the four functional domains. These four residues are known as the DEKA motif.<ref name=pmid9382897>{{cite journal | vauthors = Sun YM, Favre I, Schild L, Moczydlowski E | title = On the structural basis for size-selective permeation of organic cations through the voltage-gated sodium channel. Effect of alanine mutations at the DEKA locus on selectivity, inhibition by Ca2+ and H+, and molecular sieving | journal = The Journal of General Physiology | volume = 110 | issue = 6 | pages = 693–715 | date = December 1997 | pmid = 9382897 | pmc = 2229404 | doi = 10.1085/jgp.110.6.693 }}</ref> The permeation rate of sodium through the sodium channel is determined by a four carboxylate residues, the EEDD motif, which make up the outer charged ring.<ref name=pmid9382897/> The protonation of these carboxylates is one of the main drivers of proton block in sodium channels, although there are other residues that also contribute to pH sensitivity.<ref name=pmid12181282>{{cite journal | vauthors = Khan A, Romantseva L, Lam A, Lipkind G, Fozzard HA | title = Role of outer ring carboxylates of the rat skeletal muscle sodium channel pore in proton block | journal = The Journal of Physiology | volume = 543 | issue = Pt 1 | pages = 71–84 | date = August 2002 | pmid = 12181282 | pmc = 2290475 | doi = 10.1113/jphysiol.2002.021014 }}</ref> One such residue is C373 in the [[cardiac sodium channel]] which makes it the most pH-sensitive sodium channel among the sodium channels that have been studied to date.<ref name=pmid22701426>{{cite journal | vauthors = Vilin YY, Peters CH, Ruben PC | title = Acidosis differentially modulates inactivation in na(v)1.2, na(v)1.4, and na(v)1.5 channels | journal = Frontiers in Pharmacology | volume = 3 | pages = 109 | year = 2012 | pmid = 22701426 | pmc = 3372088 | doi = 10.3389/fphar.2012.00109 | doi-access = free }}</ref>

===pH modulation of sodium channel gating===
As the cardiac sodium channel is the most pH-sensitive sodium channel, most of what is known is based on this channel. Reduction in extracellular pH has been shown to depolarize the voltage-dependence of activation and inactivation to more positive potentials. This indicates that during activities that decrease the blood pH, such as exercising, the probability of channels activating and inactivating is higher more positive membrane potentials, which can lead to potential adverse effects.<ref name=pmid23283979>{{cite journal | vauthors = Jones DK, Peters CH, Allard CR, Claydon TW, Ruben PC | title = Proton sensors in the pore domain of the cardiac voltage-gated sodium channel | journal = The Journal of Biological Chemistry | volume = 288 | issue = 7 | pages = 4782–91 | date = February 2013 | pmid = 23283979 | pmc = 3576083 | doi = 10.1074/jbc.M112.434266 | doi-access = free }}</ref> The sodium channels expressed in skeletal muscle fibers have evolved into relatively pH-insensitive channels. This has been suggested to be a protective mechanism against potential over- or under-excitability in skeletal muscles, as blood pH levels are highly susceptible to change during movement.<ref name=pmid16873405>{{cite journal | vauthors = Khan A, Kyle JW, Hanck DA, Lipkind GM, Fozzard HA | title = Isoform-dependent interaction of voltage-gated sodium channels with protons | journal = The Journal of Physiology | volume = 576 | issue = Pt 2 | pages = 493–501 | date = October 2006 | pmid = 16873405 | pmc = 1890365 | doi = 10.1113/jphysiol.2006.115659 }}</ref><ref name=pmid5010039>{{cite journal | vauthors = Hermansen L, Osnes JB | title = Blood and muscle pH after maximal exercise in man | journal = Journal of Applied Physiology | volume = 32 | issue = 3 | pages = 304–8 | date = March 1972 | pmid = 5010039 | doi = 10.1152/jappl.1972.32.3.304 }}</ref> Recently, a mixed syndrome mutation that causes periodic paralysis and myotonia in the skeletal sodium channel has been shown to impart pH-sensitivity in this channel, making the gating of this channel similar to that of the cardiac subtype.<ref name=pmid29674667>{{cite journal | vauthors = Ghovanloo MR, Abdelsayed M, Peters CH, Ruben PC | title = A Mixed Periodic Paralysis & Myotonia Mutant, P1158S, Imparts pH-Sensitivity in Skeletal Muscle Voltage-gated Sodium Channels | journal = Scientific Reports | volume = 8 | issue = 1 | pages = 6304 | date = April 2018 | pmid = 29674667 | pmc = 5908869 | doi = 10.1038/s41598-018-24719-y | bibcode = 2018NatSR...8.6304G }}</ref>

===pH modulation across the subtypes studied thus far===
The effects of protonation have been characterized in Na<sub>v</sub>1.1–Na<sub>v</sub>1.5. Among these channels, Na<sub>v</sub>1.1–Na<sub>v</sub>1.3 and Na<sub>v</sub>1.5 display depolarized voltage-dependence of activation, while activation in Na<sub>v</sub>1.4 remains insensitive to acidosis. The voltage-dependence of steady-state fast inactivation is unchanged in Na<sub>v</sub>1.1–Na<sub>v</sub>1.4, but steady-state fast inactivation in Na<sub>v</sub>1.5 is depolarized. Hence, among the sodium channels that have been studied so far, Na<sub>v</sub>1.4 is the least and Na<sub>v</sub>1.5 is the most proton-sensitive subtypes.<ref>{{cite journal | vauthors = Ghovanloo MR, Peters CH, Ruben PC | title = Effects of acidosis on neuronal voltage-gated sodium channels: Nav1.1 and Nav1.3 | journal = Channels | volume = 12 | issue = 1 | pages = 367–377 | date = October 2018 | pmid = 30362397 | pmc = 6284583 | doi = 10.1080/19336950.2018.1539611 }}</ref>

== See also ==

{{colbegin}}
* {{annotated link|Calcium channel}}
* {{annotated link|Chronaxie}}
* {{annotated link|Epithelial sodium channel}}
* {{annotated link|Ion channel}}
* {{annotated link|Resting ion channel}}
* {{annotated link|Sodium in biology}}
{{colend}}

== References ==
{{Reflist|32em}}

== External links ==
* {{MeshName|Sodium+Channels}}
* {{cite web | url = http://www.iuphar-db.org/IC/FamilyMenuForward?familyId=10 | title = Voltage-Gated Sodium Channels | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2008-12-18 | archive-date = 2021-12-09 | archive-url = https://web.archive.org/web/20211209142324/https://www.iuphar-db.org/IC/FamilyMenuForward?familyId=10 | url-status = dead }}

{{Ion channels|g2}}
{{ion channel modulators}}

[[Category:Electrophysiology]]
[[Category:Integral membrane proteins]]
[[Category:Sodium channels]]