Sodium channel
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Boghog2
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/* Alpha subunits */ added link to [[SCN10A|Na<sub>v</sub>α1.8]]
'''Sodium channels''' are [[integral membrane protein]]s that form [[ion channels]], conducting sodium ions ([[sodium|Na<sup>+</sup>]]) through a [[cell (biology)|cell's]] [[plasma 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 = 4<sup>th</sup> ed.| pages = pp.154-169 | isbn = 0-8385-7701-6 | oclc = | doi = }}</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 = 3<sup>rd</sup> ed. | pages = pp. 73-77 | isbn = 0-87893-321-2 | oclc = | doi = }}</ref> They are classified according to the trigger that opens the channel for such ions, i.e. either a voltage-change (voltage-gated sodium channels) or binding of a substance (a [[ligand]]) to the channel (ligand-gated sodium channels).
In excitable cells such as [[neuron]]s, [[muscle|myocytes]], and certain types of [[glia]], sodium channels are responsible for the rising phase of [[action potentials]].
==Voltage-gated==
=== Structure ===
[[Image:Alphasubunit sodium channel.png|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 |author=Yu FH, Catterall WA|title=Overview of the voltage-gated sodium channel family|journal= Genome Biol |volume= 4 |issue= 3 |pages= 207 |year= 2003|doi = 10.1186/gb-2003-4-3-207 |pmid= 12620097}}</ref>]]
Sodium channels can often be isolated from cells as a complex of two types of protein subunits, α and β. An α subunit forms the core of the channel. When the α subunit protein is expressed by a cell, it is able to form channels which conduct Na<sup>+</sup> in a voltage-gated way, even if β subunits are not expressed. When β subunits 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 [[conservation (genetics)|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.
=== Gating ===
Voltage-gated sodium channels have three types of states: deactivated (closed), activated (open), and inactivated (closed). Channels in the deactivated state are thought to be blocked on their intracellular side by an "activation gate", which is removed in response to stimulation that opens the channel. The ability to inactivate is thought to be due to a tethered plug (formed by domains III and IV of the alpha subunit), called an inactivation gate, that blocks the inside of the channel shortly after it has been activated. During an action potential the channel remains inactivated for a few [[millisecond]]s after depolarization. The inactivation is removed when the membrane potential of the cell repolarizes following the falling phase of the action potential. This allows the channels to be activated again during the next action potential. Genetic diseases that alter sodium channel inactivation can cause muscle stiffness or epileptic seizures because of the introduction of a so-called window current, during which sodium channels are tonically active, causing muscle and/or nerve cells to become over-excited.
The temporal behaviour of sodium 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 [[State (physics)|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.
=== Impermeability to other ions===
The [[pore]] of sodium channels contains a [[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. Differently sized ions also cannot interact as well with the negatively charged [[glutamate|glutamic acid]] residues that line the pore.
=== Diversity ===
Voltage-gated sodium channels normally consist of an alpha subunit which forms the ion conduction pore and one to two beta subunits which have several functions including modulation of channel gating.<ref name="Isom">{{cite journal |author=Isom LL|title=Sodium channel beta subunits: anything but auxiliary|journal= Neuroscientist |volume= 7 |issue= 1 |pages= 42–54 |year= 2001 |pmid= 11486343}}</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.]]
The family of sodium channels has nine known members, with amino acid identity >50% in the transmembrane and extracellular loop regions. A standardized nomenclature for sodium channels is currently used and is maintained by the [[IUPHAR]].<ref>[http://www.iuphar.org IUPHAR - International Union of Basic and Clinical Pharmacology<!-- Bot generated title -->]</ref><ref name="Catterall">{{cite journal |author=Catterall WA, Goldin AL, Waxman SG|title=International Union of Pharmacology. XLVII. Nomenclature and structure-function relationships of voltage-gated sodium channels.|journal= Pharmacol Rev |volume= 57 |issue= 4 |pages= 397–409 |year= 2005|doi = 10.1124/pr.57.4.4 |pmid= 16382098}}</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 SCN11A (the SCN6/7A gene is part of the Na<sub>x</sub> sub-family and has uncertain function). The likely 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.
{| class="wikitable" style="text-align:center"
|+ '''Table 1.''' Nomenclature and some function of voltage-gated sodium channels
|-
! Protein name !! Gene !! Auxiliary subunits !! Expression profile !! Associated human [[Channelopathy|channelopathies]]
|-
! [[Nav1.1|Na<sub>v</sub>α1.1]]
| {{Gene|SCN1A}} || β1,β2,β3,β4 || [[Central neurons]] and [[cardiac myocytes]] || Inherited febrile [[epilepsy]], [[Generalized epilepsy with febrile seizures|GEFS]] and [[myoclonic epilepsy]]
|-
! [[Nav1.2|Na<sub>v</sub>α1.2]]
| {{Gene|SCN2A}} || β1,β2,β3,β4 || Central neurons || inherited [[Seizures, febrile|febrile seizures]] and [[epilepsy]]
|-
! [[SCN3A|Na<sub>v</sub>α1.3]]
| {{Gene|SCN3A}} || β1,β3 || Central neurons and cardiac myocytes || none known
|-
! [[Nav1.4|Na<sub>v</sub>α1.4]]
| {{Gene|SCN4A}} || β1 || [[Skeletal muscle]] || [[hyperkalemic periodic paralysis]], [[Paramyotonia congenita]], and [[potassium-aggravated myotonia]]
|-
! [[Nav1.5|Na<sub>v</sub>α1.5]]
| {{Gene|SCN5A}} || β1,β2,β3,β4 || Central neurons, cardiac myocytes || [[Long QT Syndrome]], [[Brugada|Brugada syndrome]], and idiopathic [[ventricular fibrillation]]
|-
! [[SCN8A|Na<sub>v</sub>α1.6]]
| {{Gene|SCN8A}} || β1,β2 || Central neurons, [[dorsal root ganglia]], [[peripheral neurons]] || none known
|-
! [[Nav1.7|Na<sub>v</sub>α1.7]]
| {{Gene|SCN9A}} || β1,β2 || [[Dorsal root ganglia]], sympathetic neurons, [[Schwann cells]], and [[neuroendocrine cells]] || [[Erythromelalgia]] and [[Channelopathy-associated insensitivity to pain]]
|-
! [[SCN10A|Na<sub>v</sub>α1.8]]
| {{Gene|SCN10A}} || unknown || Dorsal root ganglia || none known
|-
! [[Nav1.9|Na<sub>v</sub>α1.9]]
| {{Gene|SCN11A}} || unknown || Dorsal root ganglia || none known
|-
! [[SCN7A]]
| {{Gene|SCN7A}} || unknown || unknown || none known
|}
==== Beta subunits ====
In addition to regulating channel gating, sodium channel beta subunits also modulate channel expression and form links to the [[Intracellular|intracelluar]] [[cytoskeleton]] and [[extracellular matrix]].<ref name="Isom">{{cite journal |author=Isom LL|title=Sodium channel beta subunits: anything but auxiliary|journal= Neuroscientist |volume= 7 |issue= 1 |pages= 42–54 |year= 2001 |pmid= 11486343}}</ref>
{| class="wikitable" style="text-align:center"
| '''Protein name''' || '''Gene link'''
|-
| [[SCN1B|Na<sub>v</sub>β1]] || {{Gene|SCN1B}}
|-
| [[SCN2B|Na<sub>v</sub>β2]] || {{Gene|SCN2B}}
|-
| [[SCN3B|Na<sub>v</sub>β3]] || {{Gene|SCN3B}}
|-
| [[SCN4B|Na<sub>v</sub>β4]] || {{Gene|SCN4B}}
|}
==Ligand-gated==
[[Ligand-gated]] sodium channels are activated by binding of a [[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.
== Role in action potential ==
:''See main article: [[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]] 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, creates the change in the membrane potential in the first place, in response to the binding of a ligand to it.
==Pharmacologic modulation==
===Blockers===
====Extracellular====
The following naturally produced substances block sodium channels by binding to and occluding the [[extracellular]] pore opening of the channel:
*[[Alkaloid]] based toxins
**[[tetrodotoxin]] (TTX)
**[[saxitoxin]]
====Intracellular====
Drugs which block sodium channels by blocking from the [[intracellular]] side of the channel:
* [[Local anesthetic]]s
* [[Antiarrhythmic agent#Class I agents|Class I antiarrhythmic agents]]
* Some [[anticonvulsant]]s
====Unknown mechanism====
* A-803467: specific blockade of Na<sub>v</sub>1.8 channels, developed by [[Icagen]] and [[Abbott Laboratories]]<ref name="PNASv104p8520">{{cite journal
| last = Jarvis | first = Michael F. | coauthors = Prisca Honore and 35 additional coauthors
| date = 2007-05-27 | accessdate = 2007-12-16
| title = A-803467, a potent and selective Na<sub>v</sub>1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat
| journal = [[PNAS]] | volume = 104 | issue = 20 | pages = 8520–8525
| publisher = National Academy of Sciences of the United States
| pmid = 17483457 | doi = 10.1073/pnas.0611364104 | url = http://www.pnas.org/cgi/content/full/104/20/8520
}}</ref>
* [[Caffeine]] has been shown to inhibit Na+ current in guinea pig ventricular cells.[http://www.ncbi.nlm.nih.gov/pubmed/1661092?ordinalpos=21&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum PubMed]
=== Activators ===
The following naturally produced substances persistently activate (open) sodium channels:
*[[Alkaloid]] based toxins
** [[veratridine]]
** [[batrachotoxin]]
** [[aconitine]]
*[[Diterpene]] based toxins
** [[grayanotoxin]]
=== Gating modifiers ===
The following toxins modify the gating of sodium channels:
*[[Peptide]] based toxins
**μ-[[conotoxin]]
**δ-atracotoxin<ref name=Grolleau_2000>{{cite journal |author=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=J. Exp. Biol. |volume=204 |issue=Pt 4 |pages=711–21 |year=2001 |pmid=11171353}}</ref>
== See also ==
* [[Ion channel]]s
* [[Calcium channel]]s
* [[Potassium channel]]s
* [[Resting ion channel]]s
* [[Epithelial sodium channel]]
==References==
{{Reflist|2}}
==External links==
* {{MeshName|Sodium+Channels}}
{{Ion channels}}
[[Category:ion channels]]
[[Category:Electrophysiology]]
[[Category:Sodium]]
[[Category:Integral membrane proteins]]
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