| Neurotransmitter-gated ion-channel transmembrane region | |||||||||
|---|---|---|---|---|---|---|---|---|---|
 Ligand-gated ion channel | |||||||||
| Identifiers | |||||||||
| Symbol | Neur_chan_memb | ||||||||
| Pfam | PF02932 | ||||||||
| InterPro | IPR006029 | ||||||||
| PROSITE | PDOC00209 | ||||||||
| SCOP2 | 1cek /SCOPe /SUPFAM | ||||||||
| TCDB | 1.A.9 | ||||||||
| OPM superfamily | 14 | ||||||||
| OPM protein | 2bg9 | ||||||||
| |||||||||
Ligand-gated ion channels (LICs,LGIC), also commonly referred to asionotropic receptors, are a group oftransmembraneion-channel proteins which open to allow ions such asNa+,K+,Ca2+, and/orCl− to pass through the membrane in response to the binding of a chemical messenger (i.e. aligand), such as aneurotransmitter.[1][2][3]
When apresynaptic neuron is excited, it releases aneurotransmitter from vesicles into thesynaptic cleft. The neurotransmitter then binds to receptors located on thepostsynaptic 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 adepolarization, for an excitatory receptor response, or ahyperpolarization, 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 (anallosteric 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 atsynapses is to convert the chemical signal ofpresynaptically released neurotransmitter directly and very quickly into apostsynaptic electrical signal. Many LICs are additionally modulated byallostericligands, bychannel blockers,ions, or themembrane potential. LICs are classified into three superfamilies which lack evolutionary relationship:cys-loop receptors,ionotropic glutamate receptors andATP-gated channels.
Thecys-loop receptors are named after a characteristic loop formed by a disulfide bond between twocysteine 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".[4][5]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 transmembranehelices constituting the transmembrane domain, and a beta sheet sandwich type, extracellular, N terminal, ligand binding domain.[6] Some also contain an intracellular domain like shown in the image.
The prototypic ligand-gated ion channel is thenicotinic acetylcholine receptor. It consists of a pentamer of protein subunits (typically ααβγδ), with two binding sites foracetylcholine (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 theirelectrochemical 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 anaction potential.
A bacterial homologue to an LIC has been identified, hypothesized to act nonetheless as a chemoreceptor.[4] This prokaryotic nAChR variant is known as theGLIC receptor, after the species in which it was identified;GloeobacterLigand-gatedIonChannel.
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, fourtransmembrane segments (TMSs) are connected by intracellular and extracellular loop structures.[7] 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.[7] 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, andposttranslational modifications. Motifs important for trafficking are therein, and the ICD interacts with scaffold proteins enabling inhibitorysynapse formation.[7]
| Type | Class | IUPHAR-recommended protein name[8] | 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 LICZ, LICZ1 |
| Type | Class | IUPHAR-recommended protein name[8] | 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[9] | |
| Glycine (GlyR) | alpha | α1 α2 α3 α4 | GLRA1 GLRA2 GLRA3 GLRA4 | STHE |
| beta | β | GLRB |
Theionotropic glutamate receptors bind theneurotransmitterglutamate. 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 invertedpotassium channel.
| Type | Class | IUPHAR-recommended protein name[8] | 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 |
The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known asAMPA receptor, or quisqualate receptor) is a non-NMDA-typeionotropictransmembrane receptor forglutamate that mediates fastsynaptic transmission in thecentral nervous system (CNS).Its name is derived from its ability to be activated by the artificial glutamate analogAMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonistquisqualate 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.[10] AMPARs are found in many parts of thebrain and are the most commonly found receptor in thenervous system. The AMPA receptor GluA2 (GluR2) tetramer was the first glutamate receptor ion channel to becrystallized. Ligands include:
The N-methyl-D-aspartate receptor (NMDA receptor) – a type ofionotropic glutamate receptor – is a ligand-gated ion channel that isgated by the simultaneous binding ofglutamate and a co-agonist (i.e., eitherD-serine orglycine).[11] Studies show that the NMDA receptor is involved in regulatingsynaptic plasticity and memory.[12][13]
The name "NMDA receptor" is derived from the ligandN-methyl-D-aspartate (NMDA), which acts as aselective agonist at these receptors. When the NMDA receptor is activated by the binding of two co-agonists, thecation channel opens, allowing Na+ and Ca2+ to flow into the cell, in turn raising thecell's electric potential. Thus, the NMDA receptor is an excitatory receptor. Atresting potentials, the binding of Mg2+ or Zn2+ at their extracellularbinding sites on the receptor blocks ion flux through the NMDA receptor channel. "However, when neurons are depolarized, for example, by intense activation of colocalized postsynapticAMPA receptors, 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".[14] Ligands include:
ATP-gated channels open in response to binding thenucleotideATP. 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[8] | 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 |
Ligand-gated ion channels are likely to be the major site at whichanaesthetic agents andethanol have their effects, although unequivocal evidence of this is yet to be established.[16][17] In particular, theGABA andNMDA receptors are affected byanaesthetic agents at concentrations similar to those used in clinical anaesthesia.[18]
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 orFDA.Memantine is approved by the U.S. F.D.A and the European Medicines Agency for the treatment of moderate-to-severeAlzheimer's disease,[19] and has now received a limited recommendation by the UK'sNational Institute for Health and Care Excellence for patients who fail other treatment options.[20]Agomelatine, is a type of drug that acts on a dualmelatonergic-serotonergic pathway, which have shown its efficacy in the treatment of anxious depression during clinical trials,[21][22] study also suggests the efficacy in the treatment of atypical andmelancholic depression.[23]
At membrane potentials more negative than approximately −50 mV, the Mg2+ in the extracellular fluid of the brain virtually abolishes ion flux through NMDA receptor channels, even in the presence of glutamate. ... The NMDA receptor is unique among all neurotransmitter receptors in that its activation requires the simultaneous binding of two different agonists. In addition to the binding of glutamate at the conventional agonist-binding site, the binding of glycine appears to be required for receptor activation. Because neither of these agonists alone can open this ion channel, glutamate and glycine are referred to as coagonists of the NMDA receptor. The physiologic significance of the glycine binding site is unclear because the normal extracellular concentration of glycine is believed to be saturating. However, recent evidence suggests that D-serine may be the endogenous agonist for this site.
As ofthis edit, this article uses content from"1.A.9 The Neurotransmitter Receptor, Cys loop, Ligand-gated Ion Channel (LIC) Family", which is licensed in a way that permits reuse under theCreative Commons Attribution-ShareAlike 3.0 Unported License, but not under theGFDL. All relevant terms must be followed.
