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651  structures 267  species 3  interactions 6005  sequences 90  architectures

Family: Neur_chan_LBD (PF02931)

Summary: Neurotransmitter-gated ion-channel ligand binding domain

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This is the Wikipedia entry entitled "Ligand-gated ion channel". More...

Ligand-gated ion channel Edit Wikipedia article

Neurotransmitter-gated ion-channel transmembrane region
LGIC.png
Ligand-gated ion channel
Identifiers
Symbol Neur_chan_memb
Pfam PF02932
InterPro IPR006029
PROSITE PDOC00209
SCOP 1cek
SUPERFAMILY 1cek
TCDB 1.A.9
OPM superfamily 14
OPM protein 2bg9
Illustration depicting Acetylcholine (ACh) ligand gated 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 Cl- to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand),[1] such as a neurotransmitter.[2]

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 messengers), 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).[2][3]

Cys-loop receptors[edit]

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 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.[4] 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 LGIC has been identified, hypothesized to act none the less as a chemoreceptor.[5] This prokaryotic nAChR variant is know as the GLIC receptor, after the species in which it was identified; Gloeobacter Ligand-gated Ion Channel.

Vertebrate Anionic Cys-loop Receptors

Type Class IUPHAR-recommended
protein name[6]
Gene Previous names
GABAA alpha α1
α2
α3
α4
α5
α6
GABRA1
GABRA2
GABRA3
GABRA4
GABRA5
GABRA6
EJM, ECA4
beta β1
β2
β3
GABRB1
GABRB2
GABRB3


ECA5
gamma γ1
γ2
γ3
GABRG1
GABRG2
GABRG3
CAE2, ECA2, GEFSP3
delta δ GABRD
epsilon ε GABRE
pi π GABRP
theta θ GABRQ
rho ρ1
ρ2
ρ3
GABRR1
GABRR2
GABRR3
GABAC[7]
Glycine
(GlyR)
alpha α1
α2
α3
α4
GLRA1
GLRA2
GLRA3
GLRA4
STHE

beta β GLRB

Vertebrate Cationic Cys-loop Receptors

Type Class IUPHAR-recommended
protein name [6]
Gene Previous names
Serotonin
(5-HT)
5-HT3 5-HT3A
5-HT3B
5-HT3C
5-HT3D
5-HT3E
HTR3A
HTR3B
HTR3C
HTR3D
HTR3E
5-HT3A
5-HT3B
5-HT3C
5-HT3D
5-HT3E
Nicotinic acetylcholine
(nAChR)
alpha α1
α2
α3
α4
α5
α6
α7
α9
α10
CHRNA1
CHRNA2
CHRNA3
CHRNA4
CHRNA5
CHRNA6
CHRNA7
CHRNA9
CHRNA10
ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS







beta β1
β2
β3
β4
CHRNB1
CHRNB2
CHRNB3
CHRNB4
CMS2A, SCCMS, ACHRB, CHRNB, CMS1D
EFNL3, nAChRB2

gamma γ CHRNG ACHRG
delta δ CHRND ACHRD, CMS2A, FCCMS, SCCMS
epsilon ε CHRNE ACHRE, CMS1D, CMS1E, CMS2A, FCCMS, SCCMS
Zinc-activated ion channel
(ZAC)
ZAC ZACN ZAC1, L2m LGICZ, LGICZ1

Ionotropic glutamate receptors (iGluR)[edit]

The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2

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.

Type Class IUPHAR-recommended
protein name [6]
Gene Previous names
AMPA GluA GluA1
GluA2
GluA3
GluA4
GRIA1
GRIA2
GRIA3
GRIA4
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
Kainate GluK GluK1
GluK2
GluK3
GluK4
GluK5
GRIK1
GRIK2
GRIK3
GRIK4
GRIK5
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
NMDA GluN GluN1
NRL1A
NRL1B
GRIN1
GRINL1A
GRINL1B
GLUN1, NMDA-R1, NR1, GluRξ1


GluN2A
GluN2B
GluN2C
GluN2D
GRIN2A
GRIN2B
GRIN2C
GRIN2D
GLUN2A, NMDA-R2A, NR2A, GluRε1
GLUN2B, NMDA-R2B, NR2B, hNR3, GluRε2
GLUN2C, NMDA-R2C, NR2C, GluRε3
GLUN2D, NMDA-R2D, NR2D, GluRε4
GluN3A
GluN3B
GRIN3A
GRIN3B
GLUN3A, NMDA-R3A, NMDAR-L, chi-1
GLU3B, NMDA-R3B
‘Orphan’ (GluD) GluD1
GluD2
GRID1
GRID2
GluRδ1
GluRδ2

ATP-gated channels[edit]

Figure 1. Schematic representation showing the membrane topology of a typical P2X receptor subunit. First and second transmembrane domains are labeled TM1 and TM2.

ATP-gated channels open in response to binding the nucleotide ATP. They form trimers with two transmembrane helices per subunit and both the C and N termini on the intracellular side.

Type Class IUPHAR-recommended
protein name [6]
Gene Previous names
P2X N/A P2X1
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7
P2RX1
P2RX2
P2RX3
P2RX4
P2RX5
P2RX6
P2RX7
P2X1
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7

PIP2-gated channels[edit]

Phosphatidylinositol 4,5-bisphosphate (PIP2) binds to and directly agonizes Inward rectifying potassium channels(Kir).[8] PIP2 is a plasma membrane lipid and its definitive role in gating ion channels was only recently demonstrated by X-ray crystallography.

Clinical relevance[edit]

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.[9][10] In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia.[11]

See also[edit]

References[edit]

  1. ^

    "ligand-gated channel" at Dorland's Medical Dictionary

  2. ^ a b 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. 156–7. ISBN 978-0-87893-697-7. 
  3. ^ 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): 529–34. doi:10.1042/BST0320529. PMID 15157178. 
  4. ^ Cascio M (2004). "Structure and function of the glycine receptor and related nicotinicoid receptors". J. Biol. Chem. 279 (19): 19383–6. doi:10.1074/jbc.R300035200. PMID 15023997. 
  5. ^ 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-r40. PMC 549065. PMID 15642096. 
  6. ^ a b c d Collingridge GL, Olsen RW, Peters J, Spedding M (January 2009). "A nomenclature for ligand-gated ion channels". Neuropharmacology 56 (1): 2–5. doi:10.1016/j.neuropharm.2008.06.063. PMC 2847504. PMID 18655795. 
  7. ^ Olsen RW, Sieghart W (September 2008). "International Union of Pharmacology. LXX. Subtypes of γ-Aminobutyric AcidA Receptors: Classification on the Basis of Subunit Composition, Pharmacology, and Function. Update". Pharmacol. Rev. 60 (3): 243–60. doi:10.1124/pr.108.00505. PMC 2847512. PMID 18790874. 
  8. ^ 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): 495–8. doi:10.1038/nature10370. PMC 3324908. PMID 21874019.  Unknown parameter |bib code= ignored (help);
  9. ^ Krasowski MD, Harrison NL (1999). "General anaesthetic actions on ligand-gated ion channels". Cell. Mol. Life Sci. 55 (10): 1278–303. doi:10.1007/s000180050371. PMC 2854026. PMID 10487207. 
  10. ^ Dilger JP (2002). "The effects of general anaesthetics on ligand-gated ion channels". Br J Anaesth 89 (1): 41–51. doi:10.1093/bja/aef161. PMID 12173240. 
  11. ^ 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): 1454–62. PMID 7589987. 

External links[edit]

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

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 ligand binding domain Provide feedback

This family is the extracellular ligand binding domain of these ion channels [1]. This domain forms a pentameric arrangement in the known structure.

Literature references

  1. Brejc K, van Dijk WJ, Klaassen RV, Schuurmans M, van Der Oost J, Smit AB, Sixma TK; , Nature 2001;411:269-276.: Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. PUBMED:11357122 EPMC:11357122

  2. 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


External database links

This tab holds annotation information from the InterPro database.

InterPro entry IPR006202

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 entry presents the extracellular ligand binding domain of these ion channels. This domain forms a pentameric arrangement in the known structure.

Gene Ontology

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Domain organisation

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RP35
(1272)
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  Seed
(92)
Full
(6005)
Representative proteomes NCBI
(5129)
Meta
(71)
RP15
(1010)
RP35
(1272)
RP55
(2385)
RP75
(3245)
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  Seed
(92)
Full
(6005)
Representative proteomes NCBI
(5129)
Meta
(71)
RP15
(1010)
RP35
(1272)
RP55
(2385)
RP75
(3245)
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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

External links

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Pfam alignments:

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Curation and family details

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Seed source: Prosite
Previous IDs: none
Type: Family
Author: Bateman A, Sonnhammer ELL
Number in seed: 92
Number in full: 6005
Average length of the domain: 186.70 aa
Average identity of full alignment: 25 %
Average coverage of the sequence by the domain: 43.27 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 23193494 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 25.8 25.8
Trusted cut-off 25.9 25.8
Noise cut-off 25.6 25.6
Model length: 217
Family (HMM) version: 18
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Interactions

There are 3 interactions for this family. More...

Neur_chan_memb Neur_chan_LBD Toxin_1

Structures

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_LBD domain has been found. There are 651 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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