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, potassium, calcium, and/or chloride to pass through the membrane in response to the binding of a chemical messenger (i.e. a ligand), such as a neurotransmitter.
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, 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 postsynaptic electrical signal. Many LICs are additionally modulated by allosteric ligands, by channel blockers, , or the membrane potential. LICs are classified into three superfamilies which lack evolutionary relationship: cys-loop receptors, ionotropic glutamate receptors and ATP-gated channels.
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.
A bacterial homologue to an LIC 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.
Serotonin (5-HT) | 5-HT3 | 5-HT3A 5-HT3B 5-HT3C 5-HT3D 5-HT3E | 5-HT3A 5-HT3B 5-HT3C 5-HT3D 5-HT3E | |
Nicotinic acetylcholine (nAChR) | alpha | α1 α2 α3 α4 α5 α6 α7 α9 α10 | ACHRA, ACHRD, CHRNA, CMS2A, FCCMS, SCCMS | |
beta | β1 β2 β3 β4 | CMS2A, SCCMS, ACHRB, CHRNB, CMS1D EFNL3, nAChRB2 | ||
gamma | CHRNG | ACHRG | ||
delta | CHRND | ACHRD, CMS2A, FCCMS, SCCMS | ||
epsilon | CHRNE | ACHRE, CMS1D, CMS1E, CMS2A, FCCMS, SCCMS | ||
Zinc-activated ion channel (ZAC) | ZAC | ZAC1, L2m LICZ, LICZ1 |
GABAA receptorA | alpha | α1 α2 α3 α4 α5 α6 | EJM, ECA4 | |
beta | β1 β2 β3 | ECA5 | ||
gamma | γ1 γ2 γ3 | CAE2, ECA2, GEFSP3 | ||
delta | GABRD | |||
epsilon | GABRE | |||
pi | GABRP | |||
theta | GABRQ | |||
rho | ρ1 ρ2 ρ3 | GABAC | ||
Glycine receptor (GlyR) | alpha | α1 α2 α3 α4 | STHE | |
beta | GLRB |
AMPA receptor | GluA | GluA1 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 | |
Kainate receptor | GluK | GluK1 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 | |
NMDA receptor | GluN | GluN1 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 |
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 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:
P2X | N/A | P2X1 P2X2 P2X3 P2X4 P2X5 P2X6 P2X7 | P2X1 P2X2 P2X3 P2X4 P2X5 P2X6 P2X7 | |
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 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 Agomelatine, is a type of drug that acts on a dual melatonergic-Serotonin pathway, which have shown its efficacy in the treatment of anxious depression during clinical trials,
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