Editing Ion channel (section)

===Classification by gating===

Ion channels may be classified by gating, i.e. what opens and closes the channels. For example, voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of [[Ligand (biochemistry)|ligands]] to the channel.<ref>Ravna, A.W., Sylte, I. (2011). Homology Modeling of Transporter Proteins (Carriers and Ion Channels). In: Orry, A., Abagyan, R. (eds) Homology Modeling. Methods in Molecular Biology, vol 857. Humana Press. https://doi.org/10.1007/978-1-61779-588-6_12</ref>

====Voltage-gated====

{{Main|Voltage-gated ion channel}}
Voltage-gated ion channels open and close in response to [[membrane potential]].
* [[Voltage-gated sodium channel]]s: This family contains at least 9 members and is largely responsible for [[action potential]] creation and propagation. The pore-forming α subunits are very large (up to 4,000 [[amino acid]]s) and consist of four homologous repeat domains (I-IV) each comprising six transmembrane segments (S1-S6) for a total of 24 transmembrane segments. The members of this family also coassemble with auxiliary β subunits, each spanning the membrane once.  Both α and β subunits are extensively [[glycosylation|glycosylated]].
* [[Voltage-gated calcium channel]]s: This family contains 10 members, though these are known to coassemble with α<sub>2</sub>δ, β, and γ subunits. These channels play an important role in both linking muscle excitation with contraction as well as neuronal excitation with transmitter release. The α subunits have an overall structural resemblance to those of the sodium channels and are equally large.
** [[Cation channels of sperm]]: This small family of channels, normally referred to as Catsper channels, is related to the [[two-pore channels]] and distantly related to [[Transient response potential channel|TRP channels]].
* [[Voltage-gated potassium channel]]s (K<sub>V</sub>): This family contains almost 40 members, which are further divided into 12 subfamilies. These channels are known mainly for their role in repolarizing the cell membrane following [[action potential]]s.  The α subunits have six transmembrane segments, homologous to a single domain of the sodium channels.  Correspondingly, they assemble as [[tetramer protein|tetramer]]s to produce a functioning channel.
* Some [[transient receptor potential channel]]s: This group of channels, normally referred to simply as TRP channels, is named after their role in [[Drosophila]] phototransduction. This family, containing at least 28 members, is incredibly diverse in its method of activation. Some TRP channels seem to be constitutively open, while others are gated by [[Voltage-gated ion channel|voltage]], intracellular [[Calcium in biology|Ca<sup>2+</sup>]], pH, redox state, osmolarity, and [[Stretch-activated ion channel|mechanical stretch]]. These channels also vary according to the ion(s) they pass, some being selective for Ca<sup>2+</sup> while others are less selective, acting as cation channels. This family is subdivided into 6 subfamilies based on homology: classical ([[TRPC]]), vanilloid receptors ([[TRPV]]), melastatin ([[TRPM]]), polycystins ([[TRPP]]), mucolipins ([[TRPML]]), and ankyrin transmembrane protein 1 ([[TRPA (channel)|TRPA]]).
* Hyperpolarization-activated [[cyclic nucleotide-gated channel]]s: The opening of these channels is due to [[Hyperpolarization (biology)|hyperpolarization]] rather than the depolarization required for other cyclic nucleotide-gated channels. These channels are also sensitive to the cyclic nucleotides [[Cyclic adenosine monophosphate|cAMP]] and [[Cyclic guanosine monophosphate|cGMP]], which alter the voltage sensitivity of the channel's opening. These channels are permeable to the monovalent cations K<sup>+</sup> and Na<sup>+</sup>. There are 4 members of this family, all of which form tetramers of six-transmembrane α subunits.  As these channels open under hyperpolarizing conditions, they function as [[Cardiac pacemaker|pacemaking]] channels in the heart, particularly the [[SA node]].
* [[Voltage-gated proton channel]]s: Voltage-gated proton channels open with depolarization, but in a strongly pH-sensitive manner. The result is that these channels open only when the electrochemical gradient is outward, such that their opening will only allow protons to leave cells. Their function thus appears to be acid extrusion from cells. Another important function occurs in phagocytes (e.g. [[eosinophils]], [[neutrophils]], [[macrophages]]) during the "respiratory burst."  When bacteria or other microbes are engulfed by phagocytes, the enzyme [[NADPH oxidase]] assembles in the membrane and begins to produce [[reactive oxygen species]] (ROS) that help kill bacteria.  NADPH oxidase is electrogenic, moving electrons across the membrane, and proton channels open to allow proton flux to balance the electron movement electrically.

==== Ligand-gated (neurotransmitter) ====
{{Main|Ligand-gated ion channel}}

Also known as ionotropic [[receptor (biochemistry)|receptors]], this group of channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein.<ref name="Openstax Anatomy & Physiology attribution"> {{cite book|last1=Betts|first1=J Gordon|last2=Desaix|first2=Peter|last3=Johnson|first3=Eddie|last4=Johnson|first4=Jody E|last5=Korol|first5=Oksana|last6=Kruse|first6=Dean|last7=Poe|first7=Brandon|last8=Wise|first8=James|last9=Womble|first9=Mark D|last10=Young|first10=Kelly A|title=Anatomy & Physiology|location=Houston|publisher=OpenStax CNX|isbn=978-1-947172-04-3|date=July 6, 2023|at=12.4 The Action Potential}}</ref> Ligand binding causes a conformational change in the structure of the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane. Examples of such channels include the cation-permeable [[Acetylcholine receptor|nicotinic acetylcholine receptors]], [[Glutamate receptors|ionotropic glutamate-gated receptors]], [[acid-sensing ion channel]]s (ASICs),<ref>{{cite journal | vauthors = Hanukoglu I | title = ASIC and ENaC type sodium channels: conformational states and the structures of the ion selectivity filters | journal = The FEBS Journal | volume = 284 | issue = 4 | pages = 525–545 | date = February 2017 | pmid = 27580245 | doi = 10.1111/febs.13840 | s2cid = 24402104 | url = https://zenodo.org/record/890906 }}</ref> [[P2X Receptors|ATP-gated P2X receptors]], and the anion-permeable γ-aminobutyric acid-gated [[GABA receptor|GABA<sub>A</sub> receptor]].

Ion channels activated by second messengers may also be categorized in this group, although [[Ligand (biochemistry)|ligands]] and second messengers are otherwise distinguished from each other.{{cn|date=August 2024}}

==== Lipid-gated ====
{{Main|Lipid-gated ion channels}}

This group of channels opens in response to specific [[lipid]] molecules binding to the channel's transmembrane domain typically near the inner leaflet of the plasma membrane.<ref>{{cite journal | vauthors = Hansen SB | title = Lipid agonism: The PIP2 paradigm of ligand-gated ion channels | journal = Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids | volume = 1851 | issue = 5 | pages = 620–8 | date = May 2015 | pmid = 25633344 | pmc = 4540326 | doi = 10.1016/j.bbalip.2015.01.011 }}</ref> Phosphatidylinositol 4,5-bisphosphate ([[Phosphatidylinositol 4,5-bisphosphate|PIP<sub>2</sub>]]) and phosphatidic acid ([[Phosphatidic acid|PA]]) are the best-characterized lipids to gate these channels.<ref>{{cite journal | vauthors = Hansen SB, Tao X, MacKinnon R | title = Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2 | journal = Nature | volume = 477 | issue = 7365 | pages = 495–8 | date = August 2011 | pmid = 21874019 | pmc = 3324908 | doi = 10.1038/nature10370 | bibcode = 2011Natur.477..495H }}</ref><ref>{{cite journal | vauthors = Gao Y, Cao E, Julius D, Cheng Y | title = TRPV1 structures in nanodiscs reveal mechanisms of ligand and lipid action | journal = Nature | volume = 534 | issue = 7607 | pages = 347–51 | date = June 2016 | pmid = 27281200 | pmc = 4911334 | doi = 10.1038/nature17964 | bibcode = 2016Natur.534..347G }}</ref><ref>{{cite journal | vauthors = Cabanos C, Wang M, Han X, Hansen SB | title = 2 Antagonism of TREK-1 Channels | journal = Cell Reports | volume = 20 | issue = 6 | pages = 1287–1294 | date = August 2017 | pmid = 28793254 | pmc = 5586213 | doi = 10.1016/j.celrep.2017.07.034 }}</ref> Many of the leak potassium channels are gated by lipids including the [[Inward-rectifier potassium ion channel|inward-rectifier potassium channels]] and two pore domain potassium channels TREK-1 and TRAAK. [[KCNQ channels|KCNQ potassium channel family]] are gated by PIP<sub>2</sub>.<ref>{{cite journal | vauthors = Brown DA, Passmore GM | title = Neural KCNQ (Kv7) channels | journal = British Journal of Pharmacology | volume = 156 | issue = 8 | pages = 1185–95 | date = April 2009 | pmid = 19298256 | pmc = 2697739 | doi = 10.1111/j.1476-5381.2009.00111.x }}</ref> The voltage activated potassium channel (Kv) is regulated by PA. Its midpoint of activation shifts +50 mV upon PA hydrolysis, near resting membrane potentials.<ref>{{cite journal | vauthors = Hite RK, Butterwick JA, MacKinnon R | title = Phosphatidic acid modulation of Kv channel voltage sensor function | journal = eLife | volume = 3 | date = October 2014 | pmid = 25285449 | pmc = 4212207 | doi = 10.7554/eLife.04366 | doi-access = free }}</ref> This suggests Kv could be opened by lipid hydrolysis independent of voltage and may qualify this channel as dual lipid and voltage gated channel.

==== Other gating ====

Gating also includes activation and inactivation by [[second messenger]]s from the inside of the [[cell membrane]] – rather than from outside the cell, as in the case for ligands.
* Some potassium channels:
** [[Inward-rectifier potassium ion channel|Inward-rectifier potassium channels]]: These channels allow potassium ions to flow into the cell in an "inwardly rectifying" manner: potassium flows more efficiently into than out of the cell. This family is composed of 15 official and 1 unofficial member and is further subdivided into 7 subfamilies based on homology. These channels are affected by intracellular [[Adenosine triphosphate|ATP]], PIP<sub>2</sub>, and [[G-protein]] βγ subunits. They are involved in important physiological processes such as pacemaker activity in the heart, insulin release, and potassium uptake in [[glia|glial cells]]. They contain only two transmembrane segments, corresponding to the core pore-forming segments of the K<sub>V</sub> and K<sub>Ca</sub> channels. Their α subunits form tetramers.
** [[Calcium-activated potassium channel]]s: This family of channels is activated by intracellular Ca<sup>2+</sup> and contains 8 members.
** [[Tandem pore domain potassium channel]]: This family of 15 members form what are known as [[leak channel]]s, and they display [[GHK current equation|Goldman-Hodgkin-Katz]] (open) [[rectifier|rectification]]. Contrary to their common name of 'Two-pore-domain potassium channels', these channels have only one pore but two pore domains per subunit.<ref>{{cite web|url=http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=79|title=Two P domain potassium channels|publisher=[[Guide to Pharmacology]]|access-date=2019-05-28}}</ref><ref name="Rang60">{{cite book|title=Pharmacology|url=https://archive.org/details/clinicalpharmaco00frcp|url-access=limited| vauthors = Rang HP |publisher=Churchill Livingstone|year=2003|isbn=978-0-443-07145-4|edition=8th|location=Edinburgh|page=[https://archive.org/details/clinicalpharmaco00frcp/page/n74 59]}}</ref>
* [[Two-pore channel]]s include ligand-gated and voltage-gated cation channels, so-named because they contain two pore-forming subunits. As their name suggests, they have two pores.<ref>{{cite journal | vauthors = Kintzer AF, Stroud RM | title = Structure, inhibition and regulation of two-pore channel TPC1 from Arabidopsis thaliana | journal = Nature | volume = 531 | issue = 7593 | pages = 258–62 | date = March 2016 | pmid = 26961658 | pmc = 4863712 | doi = 10.1038/nature17194 | quote = Other than Ca2+ and Na+ channels that are formed by four intramolecular repeats, together forming the tetrameric channel's pore, the new channel had just two Shaker-like repeats, each of which was equipped with one pore domain. Because of this unusual topology, this channel, present in animals as well as plants, was named Two Pore Channel1 (TPC1). | bibcode = 2016Natur.531..258K | biorxiv = 10.1101/041400 }}</ref><ref>{{cite journal | vauthors = Spalding EP, Harper JF | title = The ins and outs of cellular Ca(2+) transport | journal = Current Opinion in Plant Biology | volume = 14 | issue = 6 | pages = 715–20 | date = December 2011 | pmid = 21865080 | pmc = 3230696 | doi = 10.1016/j.pbi.2011.08.001 | quote = The best candidate for a vacuolar Ca2+ release channel is TPC1, a homolog of a mammalian voltage-gated Ca2+ channel that possesses two pores and twelve membrane spans. }}</ref><ref>{{cite journal | vauthors = Brown BM, Nguyen HM, Wulff H | title = Recent advances in our understanding of the structure and function of more unusual cation channels | journal = F1000Research | volume = 8 | pages = 123 | date = 2019-01-30 | pmid = 30755796 | pmc = 6354322 | doi = 10.12688/f1000research.17163.1 | quote = Organellar two-pore channels (TPCs) are an interesting type of channel that, as the name suggests, has two pores. | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jammes F, Hu HC, Villiers F, Bouten R, Kwak JM | title = Calcium-permeable channels in plant cells | journal = The FEBS Journal | volume = 278 | issue = 22 | pages = 4262–76 | date = November 2011 | pmid = 21955583 | doi = 10.1111/j.1742-4658.2011.08369.x | s2cid = 205884593 | quote = The Arabidopsis two‐pore channel (AtTPC1) has been predicted to have 12 transmembrane helices and two pores (red lines). | doi-access = free }}</ref><ref>{{cite thesis|url=http://discovery.ucl.ac.uk/1335830/1/1335830.pdf|quote=It is believed that TPCs, with their two pores, dimerise to form a functional channel.|title=Molecular characterisation of NAADP-gated two-pore channels| first = Robert | last = Hooper | name-list-style = vanc |date=September 2011}}</ref>
* [[Light-gated ion channels|Light-gated channels]] like [[channelrhodopsin]] are directly opened by [[photon]]s.
* [[Mechanosensitive ion channel]]s open under the influence of stretch, pressure, shear, and displacement.
* [[Cyclic nucleotide-gated channels]]: This superfamily of channels contains two families: the cyclic nucleotide-gated (CNG) channels and the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. This grouping is functional rather than evolutionary.
** Cyclic nucleotide-gated channels: This family of channels is characterized by activation by either intracellular [[Cyclic adenosine monophosphate|cAMP]] or [[Cyclic guanosine monophosphate|cGMP]]. These channels are primarily permeable to monovalent cations such as K<sup>+</sup> and Na<sup>+</sup>. They are also permeable to Ca<sup>2+</sup>, though it acts to close them. There are 6 members of this family, which is divided into 2 subfamilies.
** Hyperpolarization-activated [[cyclic nucleotide-gated channels]]
* Temperature-gated channels: Members of the [[Trp channel|transient receptor potential ion channel]] superfamily, such as [[TRPV1]] or [[TRPM8]], are opened either by hot or cold temperatures.