Ligand-gated ion channel


Ligand-gated ion channels, also commonly referred to as ionotropic receptors, are a group of transmembrane ion-channel proteins which open to allow ions such as Na+, K+, Ca2+, and/or Cl− to pass through the membrane in response to the binding of a chemical messenger, 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. This modularity has enabled a 'divide and conquer' approach to finding the structure of the proteins. 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 LICs are additionally modulated by allosteric ligands, by channel blockers, ions, 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 cysteine 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 acetylcholine, serotonin, glycine, glutamate and γ-aminobutyric acid in vertebrates. The receptors are subdivided with respect to the type of ion that they conduct 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. 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, with two binding sites for acetylcholine. When the acetylcholine binds it alters the receptor's configuration 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 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 C channel.

Structure

Cys-loop receptors have structural elements that are well conserved, with a large extracellular domain harboring an alpha-helix and 10 beta-strands. Following the ECD, four transmembrane segments 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 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 synapse formation.

Cationic cys-loop receptors

Anionic cys-loop receptors

Ionotropic glutamate receptors

The ionotropic glutamate receptors bind the neurotransmitter glutamate. They form tetramers with each subunit consisting of an extracellular amino terminal domain, an extracellular ligand binding domain, and a transmembrane domain. 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.
TypeClassIUPHAR-recommended
protein name		GenePrevious names
AMPAGluAGluA1
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
KainateGluKGluK1
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
NMDAGluNGluN1
NRL1A
NRL1B

GLUN1, NMDA-R1, NR1, GluRξ1


NMDAGluNGluN2A
GluN2B
GluN2C
GluN2D


GLUN2A, NMDA-R2A, NR2A, GluRε1
GLUN2B, NMDA-R2B, NR2B, hNR3, GluRε2
GLUN2C, NMDA-R2C, NR2C, GluRε3
GLUN2D, NMDA-R2D, NR2D, GluRε4
NMDAGluNGluN3A
GluN3B
GLUN3A, NMDA-R3A, NMDAR-L, chi-1
GLU3B, NMDA-R3B
‘Orphan’GluD1
GluD2
GluRδ1
GluRδ2
‘Orphan’---

AMPA receptor

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system.
Its name is derived from its ability to be activated by the artificial glutamate analog AMPA. The receptor was first named the "quisqualate receptor" by Watkins and colleagues after a naturally occurring agonist quisqualate 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 brain and are the most commonly found receptor in the nervous system. The AMPA receptor GluA2 tetramer was the first glutamate receptor ion channel to be crystallized.
Ligands:
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 glutamate and a co-agonist. 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, 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 binding sites on the receptor blocks ion flux through the NMDA receptor channel. "However, when neurons are depolarized, for example, by intense activation of colocalized postsynaptic AMPA 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".
Ligands:
receptors are major inhibitory neurotransmitter expressed in the major interneurons in animal cortex.

GABAA receptor

are ligand-gated ion channels. GABA, the endogenous ligand for these receptors, is the major inhibitory neurotransmitter in the central nervous system. When activated, it mediates Cl– flow into the neuron, hyperpolarizing the neuron. GABAA receptors occur in all organisms that have a nervous system. Due to their wide distribution within the nervous system of mammals, they play a role in virtually all brain functions.
Various ligands can bind specifically to GABAA receptors, either activating or inhibiting the Cl– channel.
Ligands:
The pentameric 5-HT3 receptor is permeable to sodium, potassium, and calcium ions.

ATP-gated channels

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.
TypeClassIUPHAR-recommended
protein name		GenePrevious names
P2XN/AP2X1
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7





P2X1
P2X2
P2X3
P2X4
P2X5
P2X6
P2X7

PIP2-gated channels

binds to and directly activates inwardly rectifying potassium channels. PIP2 is a cell membrane lipid, and its role in gating ion channels represents a novel role for the molecule.

Indirect modulation

In contrast to ligand-gated ion channels, there are also receptor systems in which the receptor and the ion channel are separate proteins in the cell membrane, instead of a single molecule. In this case, ion channels are indirectly modulated by activation of the receptor, instead of being gated directly.

G-protein-linked receptors

Also called G protein-coupled receptor, seven-transmembrane domain receptor, 7 TM receptor, constitute a large protein family of receptors that sense molecules outside the cell and activate inside signal transduction pathways and, ultimately, cellular responses. They pass through the cell membrane 7 times.
G-protein-Linked receptors are a huge family that have hundreds of members identified. Ion-channel-linked receptors are only a part of them.
Table 1. Three major families of Trimeric G Proteins
FAMILYSOME FAMILY MEMBERSACTION MEDIATED BY FUNCTIONS
IGSαActivate adenylyl cyclase activates Ca2+ channels
GolfαActivates adenylyl cyclase in olfactory sensory neurons
IIGiαInhibits adenylyl cyclase
βγActivates K+ channels
G0βγActivates K+ channels; inactivate Ca2+ channels
α and βγActivates phospholipase C-β
Gt αActivate cyclic GMP phosphodiesterase in vertebrate rod photoreceptors
IIIGqαActivates phospholipase C-β

GABAB receptor

s are metabotropic transmembrane receptors for gamma-aminobutyric acid. They are linked via G-proteins to K+ channels, when active, they create hyperpolarized effect and lower the potential inside the cell.
Ligands:
The cyclic-adenosine monophosphate -generating enzyme adenylate cyclase is the effector of both the Gαs and Gαi/o pathways. Ten different AC gene products in mammals, each with subtle differences in tissue distribution and/or function, all catalyze the conversion of cytosolic adenosine triphosphate to cAMP, and all are directly stimulated by G-proteins of the Gαs class. Interaction with Gα subunits of the Gαi/o type, on the contrary, inhibits AC from generating cAMP. Thus, a GPCR coupled to Gαs counteracts the actions of a GPCR coupled to Gαi/o, and vice versa. The level of cytosolic cAMP may then determine the activity of various ion channels as well as members of the ser/thr-specific protein kinase A family. As a result, cAMP is considered a second messenger and PKA a secondary effector.
The effector of the Gαq/11 pathway is phospholipase C-β, which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-biphosphate into the second messengers inositol trisphosphate and diacylglycerol. IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum to elicit Ca2+ release from the ER, DAG diffuses along the plasma membrane where it may activate any membrane localized forms of a second ser/thr kinase called protein kinase C. Since many isoforms of PKC are also activated by increases in intracellular Ca2+, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca2+ also binds and allosterically activates proteins called calmodulins, which in turn go on to bind and allosterically activate enzymes such as Ca2+/calmodulin-dependent kinases.
The effectors of the Gα12/13 pathway are three RhoGEFs, which, when bound to Gα12/13 allosterically activate the cytosolic small GTPase, Rho. Once bound to GTP, Rho can then go on to activate various proteins responsible for cytoskeleton regulation such as Rho-kinase. Most GPCRs that couple to Gα12/13 also couple to other sub-classes, often Gαq/11.

Gβγ signaling

The above descriptions ignore the effects of Gβγ–signalling, which can also be important, in particular in the case of activated Gαi/o-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as G-protein-regulated inwardly rectifying K+ channels, P/Q- and N-type voltage-gated Ca2+ channels, as well as some isoforms of AC and PLC, along with some phosphoinositide-3-kinase isoforms.

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. In particular, the GABA and NMDA receptors are affected by anaesthetic 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 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.
Agomelatine, is a type of drug that acts on a dual melatonergic-serotonergic pathway, which have shown its efficacy in the treatment of anxious depression during clinical trails, study also suggests the efficacy in the treatment of atypical and melancholic depression.