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Ligand-gated ion channels ( LICs, LGIC), also commonly referred to as ionotropic receptors, are a group of proteins which open to allow ions such as , , , and/or to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a .

(2025). 9780878936977, Sinauer Associates.

When a presynaptic neuron is excited, it releases a from vesicles into the . 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 , for an excitatory receptor response, or a 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 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 is to convert the chemical signal of released neurotransmitter directly and very quickly into a electrical signal. Many LICs are additionally modulated by ligands, by , , or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.


Cys-loop receptors
The cys-loop receptors are named after a characteristic loop formed by a disulfide bond between two 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". 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 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 ααβγδ), with two binding sites for (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 .

A bacterial homologue to an LIC has been identified, hypothesized to act nonetheless as a chemoreceptor. This prokaryotic nAChR variant is known as the 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 segments (TMSs) are connected by intracellular and extracellular loop structures. 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. 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 posttranslational modifications. Motifs important for trafficking are therein, and the ICD interacts with scaffold proteins enabling inhibitory formation.


Cationic cys-loop receptors
Serotonin
(5-HT)
5-HT35-HT3A
5-HT3B
5-HT3C
5-HT3D
5-HT3E




5-HT3A
5-HT3B
5-HT3C
5-HT3D
5-HT3E
Nicotinic acetylcholine
(nAChR)
alphaα1
α2
α3
α4
α5
α6
α7
α9
α10








ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS







betaβ1
β2
β3
β4



CMS2A, SCCMS, ACHRB, CHRNB, CMS1D
EFNL3, nAChRB2

gamma ACHRG
delta ACHRD, CMS2A, FCCMS, SCCMS
epsilon ACHRE, CMS1D, CMS1E, CMS2A, FCCMS, SCCMS
Zinc-activated ion channel
(ZAC)
ZAC ZAC1, L2m LICZ, LICZ1


Anionic cys-loop receptors
Aalphaα1
α2
α3
α4
α5
α6





EJM, ECA4
betaβ1
β2
β3




ECA5
gammaγ1
γ2
γ3


CAE2, ECA2, GEFSP3
delta
epsilon
pi
theta
rhoρ1
ρ2
ρ3


GABAC

(GlyR)
alphaα1
α2
α3
α4



STHE

beta


Ionotropic glutamate receptors
The ionotropic glutamate receptors bind the . 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.
GluAGluA1
GluA2
GluA3
GluA4



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
GluKGluK1
GluK2
GluK3
GluK4
GluK5




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
GluNGluN1
NRL1A
NRL1B


GLUN1, NMDA-R1, NR1, GluRξ1


GluN2A
GluN2B
GluN2C
GluN2D



GLUN2A, NMDA-R2A, NR2A, GluRε1
GLUN2B, NMDA-R2B, NR2B, hNR3, GluRε2
GLUN2C, NMDA-R2C, NR2C, GluRε3
GLUN2D, NMDA-R2D, NR2D, GluRε4
GluN3A
GluN3B

GLUN3A, NMDA-R3A, NMDAR-L, chi-1
GLU3B, NMDA-R3B
‘Orphan’(GluD)GluD1
GluD2

GluRδ1
GluRδ2


AMPA receptor
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as , or quisqualate receptor) is a non--type ionotropic transmembrane receptor for that mediates fast transmission in the central nervous system (CNS). Its name is derived from its ability to be activated by the artificial glutamate analog . The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist 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. AMPARs are found in many parts of the and are the most commonly found receptor in the . The AMPA receptor GluA2 (GluR2) tetramer was the first glutamate receptor ion channel to be . Ligands include:


NMDA receptors
The N-methyl-D-aspartate receptor () – a type of ionotropic glutamate receptor – is a ligand-gated ion channel that is gated by the simultaneous binding of and a co-agonist (i.e., either or ).
(2025). 9780071481274, McGraw-Hill Medical.
Studies show that the NMDA receptor is involved in regulating synaptic plasticity and memory.

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 channel opens, allowing Na+ and Ca2+ to flow into the cell, in turn raising the cell's electric potential. Thus, the NMDA receptor is an excitatory receptor. At resting potentials, the binding of Mg2+ or Zn2+ at their extracellular on the receptor blocks ion flux through the NMDA receptor channel. "However, when neurons are depolarized, for example, by intense activation of colocalized postsynaptic , 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". Ligands include:


ATP-gated channels
ATP-gated channels open in response to binding the ATP. They form trimers with two transmembrane helices per subunit and both the C and N termini on the intracellular side.
P2XN/AP2X1
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7






P2X1
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7


Clinical relevance
Ligand-gated ion channels are likely to be the major site at which agents and have their effects, although unequivocal evidence of this is yet to be established. In particular, the and receptors are affected by agents at concentrations similar to those used in clinical anaesthesia.

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 . is approved by the U.S. F.D.A and the European Medicines Agency for the treatment of moderate-to-severe Alzheimer's disease, 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.NICE technology appraisal January 18, 2011 Azheimer's disease - donepezil, galantamine, rivastigmine and memantine (review): final appraisal determination , is a type of drug that acts on a dual - pathway, which have shown its efficacy in the treatment of anxious depression during clinical trials,

(2025). 9780071624428, McGraw-Hill.
study also suggests the efficacy in the treatment of atypical and melancholic depression.


See also
  • Acid-sensing ion channel
  • Calcium-activated potassium channel
  • Cyclic nucleotide-gated ion channel
  • Voltage-dependent calcium channel
  • Receptor (biochemistry)
  • Inositol trisphosphate receptor
  • Metabotropic receptor
  • Ryanodine receptor


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