Ligand-gated ion channel

2021-06-27T18:39:47Z

73.115.226.103: /* External links */

{{Hatnote|"Ionotropic" redirects here, not to be confused with [[inotropic]].}}
{{Short description|type of ion channel transmembrane protein}}
{{Pfam_box
| Symbol = Neur_chan_memb
| Name = Neurotransmitter-gated ion-channel transmembrane region
| image = LGIC.png
| width =
| caption = Ligand-gated ion channel
| Pfam = PF02932
| InterPro = IPR006029
| SMART =
| PROSITE = PDOC00209
| SCOP = 1cek
| TCDB = 1.A.9
| OPM family = 14
| OPM protein = 2bg9
}}
[[File:Ion-Channel Receptor.svg|thumb|{{ordered list |1=Ion-channel-linked receptor |2=[[Ions]] |3=[[Ligand]] (such as [[acetylcholine]])}} When ligands bind to the receptor, the [[ion channel]] portion of the receptor opens, allowing ions to pass across the [[cell membrane]].]]

[[File:Ligand-gated ion channel.webm|thumb|Ligand-gated ion channel showing the binding of transmitter (Tr) and changing of membrane potential (Vm)]]

'''Ligand-gated ion channels''' ('''LICs''', '''LGIC'''), also commonly referred to as '''ionotropic receptors''', are a group of [[transmembrane]] [[ion-channel]] proteins which open to allow ions such as [[sodium|Na+]], [[potassium|K+]], [[calcium|Ca2+]], and/or [[chloride|Cl−]] to pass through the membrane in response to the binding of a chemical messenger (i.e. a [[ligand (biochemistry)|ligand]]), such as a [[neurotransmitter]].<ref>{{cite web|url=https://www.genenames.org/cgi-bin/genefamilies/set/161|title=Gene Family: Ligand gated ion channels|publisher=HUGO Gene Nomenclature Committee}}</ref><ref>{{DorlandsDict|two/000019817|ligand-gated channel}}</ref><ref name="Purves" >{{cite book | author = Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White | title = Neuroscience. 4th ed. | publisher = Sinauer Associates | pages = 156–7 | year = 2008 | isbn = 978-0-87893-697-7}}</ref>

When a [[presynaptic neuron]] is excited, it releases a [[neurotransmitter]] from vesicles into the [[synaptic cleft]]. The neurotransmitter then binds to receptors located on the [[postsynaptic neuron]]. If these receptors are ligand-gated ion channels, a resulting conformational change opens the ion channels, which leads to a flow of ions across the cell membrane. This, in turn, results in either a [[depolarization]], for an excitatory receptor response, or a [[hyperpolarization (biology)|hyperpolarization]], for an inhibitory response.

These receptor proteins are typically composed of at least two different domains: a transmembrane domain which includes the ion pore, and an extracellular domain which includes the ligand binding location (an [[allosteric regulation|allosteric]] binding site). This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins (crystallising each domain separately). The function of such receptors located at [[synapse]]s is to convert the chemical signal of [[presynaptic]]ally released neurotransmitter directly and very quickly into a [[postsynaptic]] electrical signal. Many LICs are additionally modulated by [[allosteric]] [[Ligand (biochemistry)|ligands]], by [[channel blockers]], [[ion]]s, or the [[membrane potential]]. LICs are classified into three superfamilies which lack evolutionary relationship: [[cys-loop receptor]]s, [[Glutamate-gated ion channel family|ionotropic glutamate receptors]] and [[P2X purinoreceptor|ATP-gated channels]].

==Cys-loop receptors==
[[Image:2bg9 opm.gif|right|thumb|200px|Nicotinic acetylcholine receptor in closed state with predicted membrane boundaries shown, PDB 2BG9]]

The [[cys-loop receptors]] are named after a characteristic loop formed by a disulfide bond between two [[cysteine]] residues in the N terminal extracellular domain.
They are part of a larger family of pentameric ligand-gated ion channels that usually lack this disulfide bond, hence the tentative name "Pro-loop receptors".<ref name="pmid15642096">{{cite journal | vauthors = Tasneem A, Iyer LM, Jakobsson E, Aravind L | title = Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels | journal = Genome Biology | volume = 6 | issue = 1 | pages = R4 | year = 2004 | pmid = 15642096 | pmc = 549065 | doi = 10.1186/gb-2004-6-1-r4 }}</ref><ref name="pmid26986966">{{cite journal | vauthors = Jaiteh M, Taly A, Hénin J | title = Evolution of Pentameric Ligand-Gated Ion Channels: Pro-Loop Receptors | journal = PLOS ONE | volume = 11 | issue = 3 | pages = e0151934 | year = 2016 | pmid = 26986966 | pmc = 4795631 | doi = 10.1371/journal.pone.0151934 | bibcode = 2016PLoSO..1151934J }}</ref>
A binding site in the extracellular N-terminal ligand-binding domain gives them receptor specificity for (1) acetylcholine (AcCh), (2) serotonin, (3) glycine, (4) glutamate and (5) γ-aminobutyric acid (GABA) in vertebrates. The receptors are subdivided with respect to the type of ion that they conduct (anionic or cationic) and further into families defined by the endogenous ligand. They are usually pentameric with each subunit containing 4 transmembrane [[alpha helix|helices]] constituting the transmembrane domain, and a beta sheet sandwich type, extracellular, N terminal, ligand binding domain.<ref name="pmid15023997">{{cite journal | vauthors = Cascio M | title = Structure and function of the glycine receptor and related nicotinicoid receptors | journal = The Journal of Biological Chemistry | volume = 279 | issue = 19 | pages = 19383–6 | date = May 2004 | pmid = 15023997 | doi = 10.1074/jbc.R300035200 | doi-access = free }}</ref> Some also contain an intracellular domain like shown in the image.

The prototypic ligand-gated ion channel is the [[nicotinic acetylcholine receptor]]. It consists of a pentamer of protein subunits (typically ααβγδ), with two binding sites for [[acetylcholine]] (one at the interface of each alpha subunit). When the acetylcholine binds it alters the receptor's configuration (twists the T2 helices which moves the leucine residues, which block the pore, out of the channel pathway) and causes the constriction in the pore of approximately 3 angstroms to widen to approximately 8 angstroms so that ions can pass through. This pore allows Na+ ions to flow down their [[electrochemical gradient]] into the cell. With a sufficient number of channels opening at once, the inward flow of positive charges carried by Na+ ions depolarizes the postsynaptic membrane sufficiently to initiate an [[action potential]].

While single-cell organisms like bacteria would have little apparent need for the transmission of an action potential, a bacterial homologue to an LIC has been identified, hypothesized to act nonetheless as a chemoreceptor.<ref name="pmid15642096"/> This prokaryotic nAChR variant is known as the [[GLIC]] receptor, after the species in which it was identified; Gloeobacter Ligand-gated Ion Channel.

=== Structure ===
Cys-loop receptors have structural elements that are well conserved, with a large extracellular domain (ECD) harboring an alpha-helix and 10 beta-strands. Following the ECD, four [[Transmembrane domain|transmembrane segments]] (TMSs) are connected by intracellular and extracellular loop structures.<ref name=":0">{{cite journal | vauthors = Langlhofer G, Villmann C | title = The Intracellular Loop of the Glycine Receptor: It's not all about the Size | journal = Frontiers in Molecular Neuroscience | volume = 9 | pages = 41 | date = 2016-01-01 | pmid = 27330534 | pmc = 4891346 | doi = 10.3389/fnmol.2016.00041 }}</ref> Except the TMS 3-4 loop, their lengths are only 7-14 residues. The TMS 3-4 loop forms the largest part of the intracellular domain (ICD) and exhibits the most variable region between all of these homologous receptors. The ICD is defined by the TMS 3-4 loop together with the TMS 1-2 loop preceding the ion channel pore.<ref name=":0" /> Crystallization has revealed structures for some members of the family, but to allow crystallization, the intracellular loop was usually replaced by a short linker present in prokaryotic cys-loop receptors, so their structures as not known. Nevertheless, this intracellular loop appears to function in desensitization, modulation of channel physiology by pharmacological substances, and [[Post-translational modification|posttranslational modifications]]. Motifs important for trafficking are therein, and the ICD interacts with scaffold proteins enabling inhibitory [[synapse]] formation.<ref name=":0" />

===Cationic cys-loop receptors===
{| class="wikitable"
|-
|-
! Type
! Class
! IUPHAR-recommended protein name <ref name="IUPHAR"/>
! Gene
! Previous names
|-
| align="center" | [[Serotonin receptor|Serotonin]] (5-HT)
| align="center" | [[5-HT3 receptor|5-HT3]]
| align="center" | [[HTR3A|5-HT3A]] [[HTR3B|5-HT3B]] [[HTR3C|5-HT3C]] [[HTR3D|5-HT3D]] [[HTR3E|5-HT3E]]
| align="center" | {{Gene|HTR3A}} {{Gene|HTR3B}} {{Gene|HTR3C}} {{Gene|HTR3D}} {{Gene|HTR3E}}
| align="center" | 5-HT3A 5-HT3B 5-HT3C 5-HT3D 5-HT3E
|-
| rowspan = "5" align="center" | [[Nicotinic acetylcholine receptor|Nicotinic acetylcholine]] (nAChR)
| align="center" | alpha
| align="center" | [[CHRNA1|α1]] [[CHRNA2|α2]] [[CHRNA3|α3]] [[CHRNA4|α4]] [[CHRNA5|α5]] [[CHRNA6|α6]] [[CHRNA7|α7]] [[CHRNA9|α9]] [[CHRNA10|α10]]
| align="center" | {{Gene|CHRNA1}} {{Gene|CHRNA2}} {{Gene|CHRNA3}} {{Gene|CHRNA4}} {{Gene|CHRNA5}} {{Gene|CHRNA6}} {{Gene|CHRNA7}} {{Gene|CHRNA9}} {{Gene|CHRNA10}}
| align="center" |ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS 
|-
| align="center" | beta
| align="center" | [[CHRNB1|β1]] [[CHRNB2|β2]] [[CHRNB3|β3]] [[CHRNB4|β4]]
| align="center" | {{Gene|CHRNB1}} {{Gene|CHRNB2}} {{Gene|CHRNB3}} {{Gene|CHRNB4}}
| align="center" |CMS2A, SCCMS, ACHRB, CHRNB, CMS1D EFNL3, nAChRB2 
|-
| align="center" | gamma
| align="center" | [[CHRNG|γ]]
| align="center" | {{Gene|CHRNG}}
| align="center" |ACHRG
|-
| align="center" | delta
| align="center" | [[CHRND|δ]]
| align="center" | {{Gene|CHRND}}
| align="center" |ACHRD, CMS2A, FCCMS, SCCMS
|-
| align="center" | epsilon
| align="center" | [[CHRNE|ε]]
| align="center" | {{Gene|CHRNE}}
| align="center" |ACHRE, CMS1D, CMS1E, CMS2A, FCCMS, SCCMS
|-
| align="center" | [[Zinc-activated ion channel]] (ZAC)
| align="center" |
| align="center" | ZAC
| align="center" | {{Gene|ZACN}}
| align="center" | ZAC1, L2m LICZ, LICZ1
|}

===Anionic cys-loop receptors===
{| class="wikitable"
|-
! Type
! Class
! IUPHAR-recommended protein name<ref name="IUPHAR">{{cite journal | vauthors = Collingridge GL, Olsen RW, Peters J, Spedding M | title = A nomenclature for ligand-gated ion channels | journal = Neuropharmacology | volume = 56 | issue = 1 | pages = 2–5 | date = January 2009 | pmid = 18655795 | pmc = 2847504 | doi = 10.1016/j.neuropharm.2008.06.063 }}</ref>
! Gene
! Previous names
|-
| rowspan = "8" align="center" | [[GABAA receptor|GABA]]A
| align="center" | alpha
| align="center" | [[GABRA1|α1]] [[GABRA2|α2]] [[GABRA3|α3]] [[GABRA4|α4]] [[GABRA5|α5]] [[GABRA6|α6]]
| {{Gene|GABRA1}} {{Gene|GABRA2}} {{Gene|GABRA3}} {{Gene|GABRA4}} {{Gene|GABRA5}} {{Gene|GABRA6}}
| align="center" | EJM, ECA4 
|-
| align="center" | beta
| align="center" | [[GABRB1|β1]] [[GABRB2|β2]] [[GABRB3|β3]]
| align="center" | {{Gene|GABRB1}} {{Gene|GABRB2}} {{Gene|GABRB3}}
| align="center" | ECA5
|-
| align="center" | gamma
| align="center" | [[GABRG1|γ1]] [[GABRG2|γ2]] [[GABRG3|γ3]] 
| align="center" | {{Gene|GABRG1}} {{Gene|GABRG2}} {{Gene|GABRG3}}
| align="center" | CAE2, ECA2, GEFSP3
|-
| align="center" | delta
| align="center" | [[GABRD|δ]]
| align="center" | {{Gene|GABRD}}
| align="center" |
|-
| align="center" | epsilon
| align="center" | [[GABRE|ε]]
| align="center" | {{Gene|GABRE}}
| align="center" |
|-
| align="center" | pi
| align="center" | [[GABRP|π]]
| align="center" | {{Gene|GABRP}}
| align="center" |
|-
| align="center" | theta
| align="center" | [[GABRQ|θ]]
| align="center" | {{Gene|GABRQ}}
| align="center" |
|-
| align="center" | rho
| align="center" | [[GABRR1|ρ1]] [[GABRR2|ρ2]] [[GABRR3|ρ3]]
| align="center" | {{Gene|GABRR1}} {{Gene|GABRR2}} {{Gene|GABRR3}}
| align="center" |GABAC<ref name="pmid18790874">{{cite journal | vauthors = Olsen RW, Sieghart W | title = International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update | journal = Pharmacological Reviews | volume = 60 | issue = 3 | pages = 243–60 | date = September 2008 | pmid = 18790874 | pmc = 2847512 | doi = 10.1124/pr.108.00505 }}</ref>
|-
| rowspan = "2" align="center" | [[Glycine receptor|Glycine]] (GlyR)
| align="center" | alpha
| align="center" | [[GLRA1|α1]] [[GLRA2|α2]] [[GLRA3|α3]] [[GLRA4|α4]]
| align="center" | {{Gene|GLRA1}} {{Gene|GLRA2}} {{Gene|GLRA3}} {{Gene|GLRA4}}
| align="center" |STHE 
|-
| align="center" | beta
| align="center" | [[GLRB|β]]
| align="center" | {{Gene|GLRB}}
| align="center" |
|}

== Ionotropic glutamate receptors ==

The [[ionotropic glutamate receptor]]s bind the [[neurotransmitter]] [[glutamic acid|glutamate]]. They form tetramers with each subunit consisting of an extracellular amino terminal domain (ATD, which is involved tetramer assembly), an extracellular ligand binding domain (LBD, which binds glutamate), and a transmembrane domain (TMD, which forms the ion channel). The transmembrane domain of each subunit contains three transmembrane helices as well as a half membrane helix with a reentrant loop. The structure of the protein starts with the ATD at the N terminus followed by the first half of the LBD which is interrupted by helices 1,2 and 3 of the TMD before continuing with the final half of the LBD and then finishing with helix 4 of the TMD at the C terminus. This means there are three links between the TMD and the extracellular domains. Each subunit of the tetramer has a binding site for glutamate formed by the two LBD sections forming a clamshell like shape. Only two of these sites in the tetramer need to be occupied to open the ion channel. The pore is mainly formed by the half helix 2 in a way which resembles an inverted [[potassium channel]].

{| class="wikitable"
|-
! Type
! Class
! IUPHAR-recommended protein name <ref name="IUPHAR"/>
! Gene
! Previous names
|-
| align="center" | [[AMPA receptor|AMPA]]
| align="center" | GluA
| align="center" | [[GRIA1|GluA1]] [[GRIA2|GluA2]] [[GRIA3|GluA3]] [[GRIA4|GluA4]]
| align="center" | {{Gene|GRIA1}} {{Gene|GRIA2}} {{Gene|GRIA3}} {{Gene|GRIA4}}
| align="center" | GLUA1, GluR1, GluRA, GluR-A, GluR-K1, HBGR1 GLUA2, GluR2, GluRB, GluR-B, GluR-K2, HBGR2 GLUA3, GluR3, GluRC, GluR-C, GluR-K3 GLUA4, GluR4, GluRD, GluR-D
|-
| align="center" | [[Kainate receptor|Kainate]]
| align="center" | GluK
| align="center" | [[GRIK1|GluK1]] [[GRIK2|GluK2]] [[GRIK3|GluK3]] [[GRIK4|GluK4]] [[GRIK5|GluK5]]
| align="center" | {{Gene|GRIK1}} {{Gene|GRIK2}} {{Gene|GRIK3}} {{Gene|GRIK4}} {{Gene|GRIK5}}
| align="center" | GLUK5, GluR5, GluR-5, EAA3 GLUK6, GluR6, GluR-6, EAA4 GLUK7, GluR7, GluR-7, EAA5 GLUK1, KA1, KA-1, EAA1 GLUK2, KA2, KA-2, EAA2
|-
| rowspan = "3" align="center" | [[NMDA receptor|NMDA]]
| rowspan = "3" align="center" | GluN
| align="center" | [[GRIN1|GluN1]] [[GRINL1A|NRL1A]] [[GRINL1B|NRL1B]]
| align="center" | {{Gene|GRIN1}} {{Gene|GRINL1A}} {{Gene|GRINL1B}}
| align="center" | GLUN1, NMDA-R1, NR1, GluRξ1 
|-
| align="center" | [[GRIN2A|GluN2A]] [[GRIN2B|GluN2B]] [[GRIN2C|GluN2C]] [[GRIN2D|GluN2D]]
| align="center" | {{Gene|GRIN2A}} {{Gene|GRIN2B}} {{Gene|GRIN2C}} {{Gene|GRIN2D}}
| align="center" | GLUN2A, NMDA-R2A, NR2A, GluRε1 GLUN2B, NMDA-R2B, NR2B, hNR3, GluRε2 GLUN2C, NMDA-R2C, NR2C, GluRε3 GLUN2D, NMDA-R2D, NR2D, GluRε4
|-
| align="center" | [[GRIN3A|GluN3A]] [[GRIN3B|GluN3B]]
| align="center" | {{Gene|GRIN3A}} {{Gene|GRIN3B}}
| align="center" | GLUN3A, NMDA-R3A, NMDAR-L, chi-1 GLU3B, NMDA-R3B
|-
| rowspan = "2" align="center" | ‘Orphan’
| rowspan = "2" align="center" | (GluD)
| align="center" | [[GRID1|GluD1]] [[GRID2|GluD2]]
| align="center" | {{Gene|GRID1}} {{Gene|GRID2}}
| align="center" | GluRδ1 GluRδ2 
|}

=== AMPA receptor ===
[[Image:AMPA receptor.png|right|thumb|400px|The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2]]
The '''α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor''' (also known as '''[[AMPA receptor]]''', or '''quisqualate receptor''') is a non-[[NMDA]]-type [[ionotropic receptor|ionotropic]] [[transmembrane receptor]] for [[glutamate]] that mediates fast [[synapse|synaptic]] transmission in the [[central nervous system]] (CNS).
Its name is derived from its ability to be activated by the artificial glutamate analog [[AMPA]]. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist [[quisqualic acid|quisqualate]] and was only later given the label "AMPA receptor" after the selective agonist developed by Tage Honore and colleagues at the Royal Danish School of Pharmacy in Copenhagen.<ref>{{cite journal | vauthors = Honoré T, Lauridsen J, Krogsgaard-Larsen P | title = The binding of [3H]AMPA, a structural analogue of glutamic acid, to rat brain membranes | journal = Journal of Neurochemistry | volume = 38 | issue = 1 | pages = 173–8 | date = January 1982 | pmid = 6125564 | doi = 10.1111/j.1471-4159.1982.tb10868.x | s2cid = 42753770 }}</ref> AMPARs are found in many parts of the [[brain]] and are the most commonly found receptor in the [[nervous system]]. The AMPA receptor GluA2 (GluR2) tetramer was the first glutamate receptor ion channel to be [[protein crystal|crystallized]].
[[File:RegulationOfAMPARTrafficking.jpg|thumb|AMPA receptor trafficking]]

'''''Ligands:'''''
* [[Agonists]]: [[Glutamate]], [[AMPA]], [[5-Fluorowillardiine]], [[Domoic acid]], [[Quisqualic acid]], etc.
* [[Antagonists]]: [[CNQX]], [[Kynurenic acid]], [[NBQX]], [[Perampanel]], [[Piracetam]], etc.
* [[Positive allosteric modulator]]s: [[Aniracetam]], [[Cyclothiazide]], [[CX-516]], [[CX-614]], etc.
* [[Negative allosteric modulator]]s: [[Ethanol]], [[Perampanel]], [[Talampanel]], [[GYKI-52,466]], etc.

=== NMDA receptors ===
[[File:Activated NMDAR.svg|thumb|Stylized depiction of an activated NMDAR]]
The N-methyl-D-aspartate receptor ([[NMDA receptor]]) – a type of [[ionotropic glutamate receptor]] – is a ligand-gated ion channel that is [[gating (electrophysiology)|gated]] by the simultaneous binding of [[glutamate]] and a co-agonist (i.e., either [[D-serine]] or [[glycine]]).<ref name="NHM-NMDA">{{cite book |vauthors=Malenka RC, Nestler EJ, Hyman SE |veditors=Sydor A, Brown RY | title = Molecular Neuropharmacology: A Foundation for Clinical Neuroscience | year = 2009 | publisher = McGraw-Hill Medical | location = New York, USA | isbn = 9780071481274 | pages = 124–125 | edition = 2nd | chapter = Chapter 5: Excitatory and Inhibitory Amino Acids | quote = At membrane potentials more negative than approximately −50 mV, the Mg2+ in the extracellular fluid of the brain virtually abolishes ion flux through NMDA receptor channels, even in the presence of glutamate. ... The NMDA receptor is unique among all neurotransmitter receptors in that its activation requires the simultaneous binding of two different agonists. In addition to the binding of glutamate at the conventional agonist-binding site, the binding of glycine appears to be required for receptor activation. Because neither of these agonists alone can open this ion channel, glutamate and glycine are referred to as coagonists of the NMDA receptor. The physiologic significance of the glycine binding site is unclear because the normal extracellular concentration of glycine is believed to be saturating. However, recent evidence suggests that D-serine may be the endogenous agonist for this site.}}</ref> Studies show that the NMDA receptor is involved in regulating [[synaptic plasticity]] and memory.<ref>{{cite journal | vauthors = Li F, Tsien JZ | title = Memory and the NMDA receptors | journal = The New England Journal of Medicine | volume = 361 | issue = 3 | pages = 302–3 | date = July 2009 | pmid = 19605837 | pmc = 3703758 | doi = 10.1056/NEJMcibr0902052 }}</ref><ref>{{cite journal | vauthors = Cao X, Cui Z, Feng R, Tang YP, Qin Z, Mei B, Tsien JZ | title = Maintenance of superior learning and memory function in NR2B transgenic mice during ageing | journal = The European Journal of Neuroscience | volume = 25 | issue = 6 | pages = 1815–22 | date = March 2007 | pmid = 17432968 | doi = 10.1111/j.1460-9568.2007.05431.x | s2cid = 15442694 }}</ref>

The name "NMDA receptor" is derived from the ligand [[N-methyl-D-aspartate]] (NMDA), which acts as a [[selective agonist]] at these receptors. When the NMDA receptor is activated by the binding of two co-agonists, the [[cation]] channel opens, allowing Na+ and Ca2+ to flow into the cell, in turn raising the [[Membrane potential|cell's electric potential]]. Thus, the NMDA receptor is an excitatory receptor. At [[resting potential]]s, the binding of Mg2+ or Zn2+ at their extracellular [[binding site]]s on the receptor blocks ion flux through the NMDA receptor channel. "However, when neurons are depolarized, for example, by intense activation of colocalized postsynaptic [[AMPA receptor]]s, the voltage-dependent block by Mg2+ is partially relieved, allowing ion influx through activated NMDA receptors. The resulting Ca2+ influx can trigger a variety of intracellular signaling cascades, which can ultimately change neuronal function through activation of various kinases and phosphatases".<ref>{{cite journal | vauthors = Dingledine R, Borges K, Bowie D, Traynelis SF | title = The glutamate receptor ion channels | journal = Pharmacological Reviews | volume = 51 | issue = 1 | pages = 7–61 | date = March 1999 | pmid = 10049997 }}</ref>

'''''Ligands:'''''
* Primary [[Endogeny (biology)|endogenous]] [[co-agonist]]s: [[glutamate]] and either [[D-serine]] or [[glycine]]
* Other [[agonists]] : [[aminocyclopropanecarboxylic acid]]; [[D-cycloserine]]; L-aspartate; [[quinolinate]], etc.
* Partial agonists : [[N-methyl-D-aspartic acid]] ([[NMDA]]); [[NRX-1074]]; 3,5-dibromo-L-phenylalanine,<ref>{{cite journal | vauthors = Yarotskyy V, Glushakov AV, Sumners C, Gravenstein N, Dennis DM, Seubert CN, Martynyuk AE | title = Differential modulation of glutamatergic transmission by 3,5-dibromo-L-phenylalanine | journal = Molecular Pharmacology | volume = 67 | issue = 5 | pages = 1648–54 | date = May 2005 | pmid = 15687225 | doi = 10.1124/mol.104.005983 | s2cid = 11672391 }}</ref> etc.
* [[Antagonists]]: [[ketamine]], [[PCP (drug)|PCP]], [[dextropropoxyphene]], [[ketobemidone]], [[tramadol]], [[kynurenic acid]] ([[endogenous]]), etc.

==GABA receptors==
[[GABA]] receptors are major inhibitory neurotransmitter expressed in the major interneurons in animal cortex.

=== GABAA receptor===
[[File:GABAA receptor schematic.png|thumb|GABAA receptor schematic]]
[[GABAA receptors|GABAA receptors]] are ligand-gated ion channels. GABA ([[gamma-Aminobutyric acid|''gamma''-aminobutyric acid]]), the endogenous ligand for these receptors, is the major inhibitory neurotransmitter in the [[central nervous system]]. When activated, it mediates Cl– flow into the neuron, hyperpolarizing the neuron. GABAA receptors occur in all organisms that have a nervous system. Due to their wide distribution within the nervous system of mammals, they play a role in virtually all brain functions.<ref>{{cite journal | vauthors = Wu C, Sun D | title = GABA receptors in brain development, function, and injury | journal = Metabolic Brain Disease | volume = 30 | issue = 2 | pages = 367–79 | date = April 2015 | pmid = 24820774 | pmc = 4231020 | doi = 10.1007/s11011-014-9560-1 }}</ref>

Various ligands can bind specifically to GABAA receptors, either activating or inhibiting the Cl– channel.

''Ligands'':
*[[Agonists]]: GABA, [[muscimol]], [[progabide]], [[gaboxadol]]
*[[Antagonists]]: [[bicuculine]], gabazine
*Partial agonist: piperidine-4-sulfonic acid

== 5-HT3 receptor ==

The pentameric [[5-HT3 receptor]] is permeable to sodium (Na), potassium (K), and calcium (Ca) ions.

== ATP-gated channels ==
[[File:SchematicP2XRSubunitV2.png|thumb|270px|Figure 1. Schematic representation showing the membrane topology of a typical P2X receptor subunit. First and second transmembrane domains are labeled TM1 and TM2.]]

{{Main|P2X receptor}}

ATP-gated channels open in response to binding the [[nucleotide]] [[Adenosine triphosphate|ATP]]. They form trimers with two transmembrane helices per subunit and both the C and N termini on the intracellular side.
{| class="wikitable"
|-
! Type
! Class
! IUPHAR-recommended protein name <ref name="IUPHAR"/>
! Gene
! Previous names
|-
| align="center" | [[P2X Receptor|P2X]]
| align="center" | N/A
| align="center" | [[P2RX1|P2X1]] [[P2RX2|P2X2]] [[P2RX3|P2X3]] [[P2RX4|P2X4]] [[P2RX5|P2X5]] [[P2RX6|P2X6]] [[P2RX7|P2X7]]
| align="center" | {{gene|P2RX1}} {{gene|P2RX2}} {{gene|P2RX3}} {{gene|P2RX4}} {{gene|P2RX5}} {{gene|P2RX6}} {{gene|P2RX7}}
| align="center" | P2X1 P2X2 P2X3 P2X4 P2X5 P2X6 P2X7
|-
|}

== PIP2-gated channels ==
[[Phosphatidylinositol 4,5-bisphosphate]] (PIP2) binds to and directly activates [[Inward-rectifier potassium ion channel|inwardly rectifying potassium channels]] (Kir).<ref name="pmid21874019">{{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> PIP2 is a cell membrane lipid, and its role in gating ion channels represents a novel role for the molecule.<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><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>
{{clear}}

==Indirect modulation==
In contrast to ligand-gated ion channels, there are also receptor systems in which the receptor and the ion channel are separate proteins in the cell membrane, instead of a single molecule. In this case, ion channels are indirectly modulated by activation of the receptor, instead of being gated directly.

=== G-protein-linked receptors ===
[[File:GPCR mechanism.png|thumb|G-protein-coupled receptor mechanism]]
Also called [[G protein-coupled receptor]], seven-transmembrane domain receptor, 7 TM receptor, constitute a large protein family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. They pass through the cell membrane 7 times.
G-protein-Linked receptors are a huge family that have hundreds of members identified. Ion-channel-linked receptors (e.g. [[GABAB]], [[NMDA]], etc.) are only a part of them.

''Table 1. Three major families of Trimeric G Proteins<ref>Lodish, Harvey. Molecular cell biology. Macmillan, 2008.</ref>''
{| class="wikitable"
|-
!FAMILY !! SOME FAMILY MEMBERS !! ACTION MEDIATED BY !! FUNCTIONS
|-
|I || GS || α || Activate adenylyl cyclase activates Ca2+ channels
|-
| || Golf || α || Activates adenylyl cyclase in olfactory sensory neurons
|-
|II || Gi || α || Inhibits adenylyl cyclase
|-
| || || βγ || Activates K+ channels
|-
| || G0 || βγ || Activates K+ channels; inactivate Ca2+ channels
|-
| || || α and βγ || Activates phospholipase C-β
|-
| || Gt (transducin) || α || Activate cyclic GMP phosphodiesterase in vertebrate rod photoreceptors
|-
|III || Gq || α || Activates phospholipase C-β
|}

====GABAB receptor====
[[GABAB receptor]]s are metabotropic transmembrane receptors for [[gamma-aminobutyric acid]]. They are linked via G-proteins to K+ channels, when active, they create [[Hyperpolarization (biology)|hyperpolarized]] effect and lower the potential inside the cell.<ref>{{cite journal | vauthors = Chen K, Li HZ, Ye N, Zhang J, Wang JJ | title = Role of GABAB receptors in GABA and baclofen-induced inhibition of adult rat cerebellar interpositus nucleus neurons in vitro | journal = Brain Research Bulletin | volume = 67 | issue = 4 | pages = 310–8 | date = October 2005 | pmid = 16182939 | doi = 10.1016/j.brainresbull.2005.07.004 | s2cid = 6433030 }}</ref>

''Ligands'':
*[[Agonists]]: [[GABA]], [[Baclofen]], [[gamma-Hydroxybutyrate]], [[Phenibut]] etc.
*Positive Allosteric Modulators: [[CGP-7930]],<ref>{{cite journal | vauthors = Urwyler S, Mosbacher J, Lingenhoehl K, Heid J, Hofstetter K, Froestl W, Bettler B, Kaupmann K | title = Positive allosteric modulation of native and recombinant gamma-aminobutyric acid(B) receptors by 2,6-Di-tert-butyl-4-(3-hydroxy-2,2-dimethyl-propyl)-phenol (CGP7930) and its aldehyde analog CGP13501 | journal = Molecular Pharmacology | volume = 60 | issue = 5 | pages = 963–71 | date = November 2001 | pmid = 11641424 | doi = 10.1124/mol.60.5.963 }}</ref> [[Fendiline]], [[BSPP (positive allosteric modulator)|BSPP]], etc.
*[[Antagonists]]:2-OH-saclofen, [[Saclofen]], [[SCH-50911]]

==== Gα signaling ====
The [[cyclic amp|cyclic-adenosine monophosphate]] (cAMP)-generating enzyme [[Adenylyl cyclase|adenylate cyclase]] is the effector of both the Gαs and Gαi/o pathways. Ten different AC gene products in mammals, each with subtle differences in [[Tissue (biology)|tissue]] distribution and/or function, all [[catalyze]] the conversion of [[cytosolic]] [[adenosine triphosphate]] (ATP) to cAMP, and all are directly stimulated by G-proteins of the Gαs class. Interaction with Gα subunits of the Gαi/o type, on the contrary, inhibits AC from generating cAMP. Thus, a GPCR coupled to Gαs counteracts the actions of a GPCR coupled to Gαi/o, and vice versa. The level of cytosolic cAMP may then determine the activity of various [[Cyclic nucleotide-gated ion channel|ion channels]] as well as members of the [[Serine/threonine-specific protein kinase|ser/thr-specific]] [[protein kinase A]] (PKA) family. As a result, cAMP is considered a [[Second messenger system|second messenger]] and PKA a secondary [[Effector (biology)|effector]].

The effector of the Gαq/11 pathway is [[Phospholipase C|phospholipase C-β]] (PLCβ), which catalyzes the cleavage of membrane-bound [[Phosphatidylinositol 4,5-bisphosphate|phosphatidylinositol 4,5-biphosphate]] (PIP2) into the second messengers [[Inositol trisphosphate|inositol (1,4,5) trisphosphate]] (IP3) and [[Diglyceride|diacylglycerol]] (DAG). IP3 acts on [[Inositol trisphosphate receptor|IP3 receptors]] found in the membrane of the [[endoplasmic reticulum]] (ER) to elicit [[ca2+|Ca2+]] release from the ER, DAG diffuses along the [[plasma membrane]] where it may activate any membrane localized forms of a second ser/thr kinase called [[protein kinase C]] (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca2+, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca2+ also binds and [[allosterically]] activates proteins called [[calmodulin]]s, which in turn go on to bind and allosterically activate enzymes such as [[Ca2+/calmodulin-dependent protein kinase|Ca2+/calmodulin-dependent kinases]] (CAMKs).

The effectors of the Gα12/13 pathway are three [[RhoGEF domain|RhoGEFs]] (p115-RhoGEF, PDZ-RhoGEF, and LARG), which, when bound to Gα12/13 allosterically activate the cytosolic [[small GTPase]], [[Rho family of GTPases|Rho]]. Once bound to GTP, Rho can then go on to activate various proteins responsible for [[cytoskeleton]] regulation such as [[Rho-associated protein kinase|Rho-kinase]] (ROCK). Most GPCRs that couple to Gα12/13 also couple to other sub-classes, often Gαq/11.

==== Gβγ signaling ====
The above descriptions ignore the effects of [[Beta-gamma complex|Gβγ]]–signalling, which can also be important, in particular in the case of activated Gαi/o-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as [[G protein-coupled inwardly-rectifying potassium channel|G-protein-regulated inwardly rectifying K+ channels]] (GIRKs), [[P-type calcium channel|P]]/[[Q-type calcium channel|Q]]- and [[N-type calcium channel|N-]]type [[Voltage-dependent calcium channel|voltage-gated Ca2+ channels]], as well as some isoforms of AC and PLC, along with some [[PI3K|phosphoinositide-3-kinase]] (PI3K) isoforms.

== Clinical relevance ==

''Ligand-gated ion channels'' are likely to be the major site at which [[anaesthetic]] agents and [[ethanol]] have their effects, although unequivocal evidence of this is yet to be established.<ref name="pmid10487207">{{cite journal | vauthors = Krasowski MD, Harrison NL | title = General anaesthetic actions on ligand-gated ion channels | journal = Cellular and Molecular Life Sciences | volume = 55 | issue = 10 | pages = 1278–303 | date = August 1999 | pmid = 10487207 | pmc = 2854026 | doi = 10.1007/s000180050371 }}</ref><ref name="pmid12173240">{{cite journal | vauthors = Dilger JP | title = The effects of general anaesthetics on ligand-gated ion channels | journal = British Journal of Anaesthesia | volume = 89 | issue = 1 | pages = 41–51 | date = July 2002 | pmid = 12173240 | doi = 10.1093/bja/aef161 | doi-access = free }}</ref> In particular, the [[GABA]] and [[NMDA]] receptors are affected by [[anaesthetic]] agents at concentrations similar to those used in clinical anaesthesia.<ref name="pmid7589987">{{cite journal | vauthors = Harris RA, Mihic SJ, Dildy-Mayfield JE, Machu TK | title = Actions of anesthetics on ligand-gated ion channels: role of receptor subunit composition | journal = FASEB Journal | volume = 9 | issue = 14 | pages = 1454–62 | date = November 1995 | pmid = 7589987 | doi = 10.1096/fasebj.9.14.7589987| s2cid = 17913232 | url = http://www.fasebj.org/cgi/content/abstract/9/14/1454 | format = abstract }}</ref>

By understanding the mechanism and exploring the chemical/biological/physical component that could function on those receptors, more and more clinical applications are proven by preliminary experiments or [[FDA]].
* '''[[Memantine]]'''
[[Memantine]] is approved by the U.S. F.D.A and the European Medicines Agency for the treatment of moderate-to-severe [[Alzheimer's disease]],<ref name=MountC2006>{{cite journal | vauthors = Mount C, Downton C | title = Alzheimer disease: progress or profit? | journal = Nature Medicine | volume = 12 | issue = 7 | pages = 780–4 | date = July 2006 | pmid = 16829947 | doi = 10.1038/nm0706-780 | doi-access = free }}</ref> and has now received a limited recommendation by the UK's [[National Institute for Health and Care Excellence]] for patients who fail other treatment options.<ref name="NICE Guidelines">NICE technology appraisal January 18, 2011 [http://www.nice.org.uk/guidance/index.jsp?action=download&o=52515 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination]</ref>
* '''[[Antidepressant]] treatment'''
[[Agomelatine]], is a type of drug that acts on a dual [[melatonergic]]-[[serotonergic]] pathway, which have shown its efficacy in the treatment of anxious depression during clinical trails,<ref>{{cite journal | last1 = Heun | first1 = R | last2 = Coral | first2 = RM | last3 = Ahokas | first3 = A | last4 = Nicolini | first4 = H | last5 = Teixeira | first5 = JM | last6 = Dehelean | first6 = P | year = 2013 | title = 1643 – Efficacy of agomelatine in more anxious elderly depressed patients. A randomized, double-blind study vs placebo | journal = European Psychiatry | volume = 28 | issue = Suppl 1| pages = 1| doi = 10.1016/S0924-9338(13)76634-3 }}</ref><ref>Brunton, L; Chabner, B; Knollman, B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. {{ISBN|978-0-07-162442-8}}.</ref> study also suggests the efficacy in the treatment of atypical and [[melancholic depression]].<ref>{{cite journal | last1 = Avedisova | first1 = A | last2 = Marachev | first2 = M | year = 2013 | title = 2639 – The effectiveness of agomelatine (valdoxan) in the treatment of atypical depression | journal = European Psychiatry | volume = 28 | issue = Suppl 1 | pages = 1| doi = 10.1016/S0924-9338(13)77272-9 }}</ref>

== See also ==
{{Portal|Biology}}
*[[Receptor (biochemistry)]]
*[[Action potential]]
*[[Voltage-dependent calcium channel]]
*[[Calcium-activated potassium channel]]
*[[Cyclic nucleotide-gated ion channel]]
*[[Acid-sensing ion channel]]
*[[Ryanodine receptor]]
*[[Inositol trisphosphate receptor]]

== References ==
{{Reflist|30em}}

==External links==
{{Commons category|Ligand-gated ion channel}}
*[http://www.ebi.ac.uk/compneur-srv/LGICdb/LGICdb.php Ligand-Gated Ion Channel database] at [[European Bioinformatics Institute]]. Verified availability April 11, 2007.
*{{cite web | url = http://www.iuphar-db.org/LGICNomenclature.jsp | title = Revised Recommendations for Nomenclature of Ligand-Gated Ion Channels | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology }}
*[http://www.esf.edu/efb/course/EFB325/lectures/29HormoneSignals.htm www.esf.edu]
*[https://www.genenames.org/ www.genenames.org]
*[https://www.guidetopharmacology.org/ www.guidetopharmacology.org]
{{CCBYSASource|sourcepath= http://www.tcdb.org/search/result.php?tc=1.a.9|sourcearticle= 1.A.9 The Neurotransmitter Receptor, Cys loop, Ligand-gated Ion Channel (LIC) Family |revision=699838558}}

{{Ion channels|g9}}
{{Ligand-gated ion channels}}
{{pharmacomodulation}}

{{DEFAULTSORT:Ligand-Gated Ion Channel}}
[[Category:Cell biology]]
[[Category:Electrophysiology]]
[[Category:Ion channels]]
[[Category:Ionotropic receptors]]
[[Category:Membrane biology]]
[[Category:Molecular neuroscience]]
[[Category:Neurochemistry]]
[[Category:Protein families]]
[[Category:Membrane proteins]]
[[Category:Transmembrane proteins]]
[[Category:Transmembrane transporters]]
[[Category:Transport proteins]]
[[Category:Integral membrane proteins]]

Wikipedia - User contributions [en]

Ligand-gated ion channel