Summary: Neurotransmitter-gated ion-channel transmembrane region
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Ligand-gated ion channel Edit Wikipedia article
|Neurotransmitter-gated ion-channel transmembrane region|
Ligand-gated ion channel
Ligand-gated ion channels (LGICs) are a group of transmembrane ion channel proteins which open to allow ions such as Na+, K+, Ca2+, or Clâˆ’ to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.
These 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 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 synapses is to convert the chemical signal of presynaptically released neurotransmitter directly and very quickly into a postsynaptic electrical signal. Many LGICs are additionally modulated by allosteric ligands, by channel blockers, ions, or the membrane potential. LGICs are classified into three superfamilies which lack evolutionary relationship: Cys-loop receptors, Ionotropic glutamate receptors and ATP-gated channels.
LGICs can be contrasted with metabotropic receptors (which use second messenger activated ion channels), voltage-gated ion channels (which open and close depending on membrane potential), and stretch-activated ion channels (which open and close depending on mechanical deformation of the cell membrane).
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 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 helices constituting the transmembrane domain, and a beta sheet sandwich type, extracellular, N terminal, ligand binding domain. 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 Î±Î±Î²Î³Î´), 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 LGIC has been identified, hypothesized to act nonetheless as a chemoreceptor. This prokaryotic nAChR variant is known as the GLIC receptor, after the species in which it was identified; Gloeobacter Ligand-gated Ion Channel.
Vertebrate Anionic Cys-loop Receptors
|CAE2, ECA2, GEFSP3|
Vertebrate Cationic Cys-loop Receptors
protein name 
|ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS
|CMS2A, SCCMS, ACHRB, CHRNB, CMS1D
|delta||Î´||CHRND||ACHRD, CMS2A, FCCMS, SCCMS|
|epsilon||Îµ||CHRNE||ACHRE, CMS1D, CMS1E, CMS2A, FCCMS, SCCMS|
|Zinc-activated ion channel
|ZAC||ZACN||ZAC1, L2m LGICZ, LGICZ1|
Ionotropic glutamate receptors (iGluR)
The ionotropic glutamate receptors bind the neurotransmitter 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 helix 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.
protein name 
|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
|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
|GLUN1, NMDA-R1, NR1, GluRÎ¾1
|GLUN2A, NMDA-R2A, NR2A, GluRÎµ1
GLUN2B, NMDA-R2B, NR2B, hNR3, GluRÎµ2
GLUN2C, NMDA-R2C, NR2C, GluRÎµ3
GLUN2D, NMDA-R2D, NR2D, GluRÎµ4
|GLUN3A, NMDA-R3A, NMDAR-L, chi-1
protein name 
Phosphatidylinositol 4,5-bisphosphate (PIP2) binds to and directly agonizes Inward rectifying potassium channels(Kir). PIP2 is a plasma membrane lipid and its definitive role in gating ion channels was only recently demonstrated by X-ray crystallography.
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. In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia.
- "ligand-gated channel" at Dorland's Medical Dictionary
- Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White (2008). Neuroscience. 4th ed. Sinauer Associates. pp. 156â€“7. ISBN 978-0-87893-697-7.
- Connolly CN, Wafford KA (2004). "The Cys-loop superfamily of ligand-gated ion channels: the impact of receptor structure on function". Biochem. Soc. Trans. 32 (Pt3): 529â€“34. doi:10.1042/BST0320529. PMID 15157178.
- Cascio M (2004). "Structure and function of the glycine receptor and related nicotinicoid receptors". J. Biol. Chem. 279 (19): 19383â€“6. doi:10.1074/jbc.R300035200. PMID 15023997.
- Tasneem A, Iyer L, Jakobsson E, Aravind L (2004). "Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels". Genome Biology 6 (1): R4. doi:10.1186/gb-2004-6-1-r4. PMC 549065. PMID 15642096.
- Collingridge GL, Olsen RW, Peters J, Spedding M (January 2009). "A nomenclature for ligand-gated ion channels". Neuropharmacology 56 (1): 2â€“5. doi:10.1016/j.neuropharm.2008.06.063. PMC 2847504. PMID 18655795.
- Olsen RW, Sieghart W (September 2008). "International Union of Pharmacology. LXX. Subtypes of Î³-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update". Pharmacol. Rev. 60 (3): 243â€“60. doi:10.1124/pr.108.00505. PMC 2847512. PMID 18790874.
- Hansen SB, Tao X, MacKinnon R (September 2011). "Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2". Nature 477 (7365): 495â€“8. Bibcode:2011Natur.477..495H. doi:10.1038/nature10370. PMC 3324908. PMID 21874019.
- Krasowski MD, Harrison NL (1999). "General anaesthetic actions on ligand-gated ion channels". Cell. Mol. Life Sci. 55 (10): 1278â€“303. doi:10.1007/s000180050371. PMC 2854026. PMID 10487207.
- Dilger JP (2002). "The effects of general anaesthetics on ligand-gated ion channels". Br J Anaesth 89 (1): 41â€“51. doi:10.1093/bja/aef161. PMID 12173240.
- Harris RA, Mihic SJ, Dildy-Mayfield JE, Machu TK (1995). "Actions of anesthetics on ligand-gated ion channels: role of receptor subunit composition" (ABSTRACT). FASEB J. 9 (14): 1454â€“62. PMID 7589987.
- Ligand-Gated Ion Channel database at European Bioinformatics Institute. Verified availability April 11, 2007.
- "Revised Recommendations for Nomenclature of Ligand-Gated Ion Channels". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.
Neurotransmitter-gated ion-channel transmembrane region Provide feedback
This family includes the four transmembrane helices that form the ion channel.
Nury H, Bocquet N, Le Poupon C, Raynal B, Haouz A, Corringer PJ, Delarue M;, J Mol Biol. 2009; [Epub ahead of print]: Crystal Structure of the Extracellular Domain of a Bacterial Ligand-Gated Ion Channel. PUBMED:19917292 EPMC:19917292
Internal database links
|SCOOP:||DUF572 Herpes_LMP1 ASFV_J13L DUF966 DUF1180 Peptidase_S49_N MCM_bind Membralin DUF2206 SOG2 DUF2500 DUF2561 TPPK_C Hid1 Shisa DUF4544 DUF4551|
External database links
|PRINTS:||PR00252 PR00253 PR00254|
This tab holds annotation information from the InterPro database.
InterPro entry IPR006029
Neurotransmitter ligand-gated ion channels are transmembrane receptor-ion channel complexes that open transiently upon binding of specific ligands, allowing rapid transmission of signals at chemical synapses [PUBMED:1721053, PUBMED:1846404]. Five of these ion channel receptor families have been shown to form a sequence-related superfamily:
- Nicotinic acetylcholine receptor (AchR), an excitatory cation channel in vertebrates and invertebrates; in vertebrate motor endplates it is composed of alpha, beta, gamma and delta/epsilon subunits; in neurons it is composed of alpha and non-alpha (or beta) subunits [PUBMED:18446614].
- Glycine receptor, an inhibitory chloride ion channel composed of alpha and beta subunits [PUBMED:15383648].
- Gamma-aminobutyric acid (GABA) receptor, an inhibitory chloride ion channel; at least four types of subunits (alpha, beta, gamma and delta) are known [PUBMED:18760291].
- Serotonin 5HT3 receptor, of which there are seven major types (5HT3-5HT7) [PUBMED:10026168].
- Glutamate receptor, an excitatory cation channel of which at least three types have been described (kainate, N-methyl-D-aspartate (NMDA) and quisqualate) [PUBMED:15165736].
These receptors possess a pentameric structure (made up of varying subunits), surrounding a central pore. All known sequences of subunits from neurotransmitter-gated ion-channels are structurally related. They are composed of a large extracellular glycosylated N-terminal ligand-binding domain, followed by three hydrophobic transmembrane regions which form the ionic channel, followed by an intracellular region of variable length. A fourth hydrophobic region is found at the C-terminal of the sequence [PUBMED:1721053, PUBMED:1846404].
This domain represents four transmembrane helices of a variety of neurotransmitter-gated ion-channels.
The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.
|Cellular component||membrane (GO:0016020)|
|Biological process||ion transport (GO:0006811)|
Below is a listing of the unique domain organisations or architectures in which this domain is found. More...
The graphic that is shown by default represents the longest sequence with a given architecture. Each row contains the following information:
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1Cannot generate PP/Heatmap alignments for seeds; no PP data available
Key: available, not generated, — not available.
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|Author:||Bateman A, Sonnhammer ELL|
|Number in seed:||50|
|Number in full:||8354|
|Average length of the domain:||171.40 aa|
|Average identity of full alignment:||22 %|
|Average coverage of the sequence by the domain:||40.91 %|
|HMM build commands:||
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 80369284 -E 1000 --cpu 4 HMM pfamseq
|Family (HMM) version:||12|
|Download:||download the raw HMM for this family|
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Unmapped species names
The tree is built by looking at each sequence in the full alignment for the family. We take the name of the species given by UniProt and try to map that to the full taxonomic tree from NCBI. In some cases, the name chosen by UniProt does not map to any node in the NCBI tree, perhaps because the chosen name is listed as a synonym or a misspelling in the NCBI taxonomy.
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The tree shows the occurrence of this domain across different species. More...
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For all of the domain matches in a full alignment, we count the number that are found on all sequences in the alignment. This total is shown in the purple box.
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There are 7 interactions for this family. More...
We determine these interactions using iPfam, which considers the interactions between residues in three-dimensional protein structures and maps those interactions back to Pfam families. You can find more information about the iPfam algorithm in the journal article that accompanies the website.
For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the Neur_chan_memb domain has been found. There are 161 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein seqence.
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