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Ionotropic

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Ionotropic

Neurotransmitter-gated ion-channel transmembrane region
Ligand-gated ion channel
Identifiers
Symbol Neur_chan_memb
Pfam InterPro PROSITE PDOC00209
SCOP SUPERFAMILY TCDB OPM superfamily OPM protein 2bg9

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


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.

Vertebrate Anionic Cys-loop Receptors

Type Class IUPHAR-recommended
protein name[5]
Gene Previous names
GABAA alpha α1
α2
α3
α4
α5
α6
GABRA6 EJM, ECA4
beta β1
β2
β3
GABRB3

ECA5
gamma γ1
γ2
γ3
GABRG3 CAE2, ECA2, GEFSP3
delta δ GABRD
epsilon ε GABRE
pi π GABRP
theta θ GABRQ
rho ρ1
ρ2
ρ3
GABRR3 GABAC[6]
Glycine
(GlyR)
alpha α1
α2
α3
α4
GLRA4 STHE

beta β GLRB

Vertebrate Cationic Cys-loop Receptors

Type Class IUPHAR-recommended
protein name [5]
Gene Previous names
Serotonin
(5-HT)
5-HT3 5-HT3A
5-HT3B
5-HT3C
5-HT3D
5-HT3E
HTR3E 5-HT3A
5-HT3B
5-HT3C
5-HT3D
5-HT3E
Nicotinic acetylcholine
(nAChR)
alpha α1
α2
α3
α4
α5
α6
α7
α9
α10
CHRNA10 ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS







beta β1
β2
β3
β4
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)


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 [5]
Gene Previous names
AMPA GluA GluA1
GluA2
GluA3
GluA4
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
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
GRINL1B GLUN1, NMDA-R1, NR1, GluRξ1


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

ATP-gated channels


Main article: P2X receptor

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 [5]
Gene Previous names
P2X N/A P2X1
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7
P2RX7 P2X1
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7

PIP2-gated channels

Phosphatidylinositol 4,5-bisphosphate (PIP2) binds to and directly agonizes Inward rectifying potassium channels(Kir).[7] PIP2 is a plasma membrane lipid and it's definitive role in gating ion channels was only recently demonstrated by X-ray crystallography.

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.[8][9] In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia.[10]

See also

References

External links

  • European Bioinformatics Institute. Verified availability April 11, 2007.
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