Ligand-gated ion channel

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"Ionotropic" redirects here, not to be confused with inotropic.
Neurotransmitter-gated ion-channel transmembrane region
LGIC.png
Ligand-gated ion channel
Identifiers
Symbol Neur_chan_memb
Pfam PF02932
InterPro IPR006029
PROSITE PDOC00209
SCOP 1cek
SUPERFAMILY 1cek
TCDB 1.A.9
OPM superfamily 14
OPM protein 2bg9
  1. Ion channel linked receptor
  2. Ions
  3. Ligand (such as acetylcholine)
When ligands bind to the receptor, the ion channel portion of the receptor opens, allowing ions to pass across the cell membrane.

Ligand-gated ion channels (LICs), (TC# 1.A.9), also commonly referred 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 (i.e. a ligand),[1] such as a neurotransmitter.[2]

When a presynaptic neuron is excited, it releases 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 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 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[edit]

Nicotinic acetylcholine receptor in closed state with predicted membrane boundaries shown, PDB 2BG9

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. Because of this extracellular N-terminal ligand-binding domain, they exhibit 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 helices constituting the transmembrane domain, and a beta sheet sandwich type, extracellular, N terminal, ligand binding domain.[3] 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.

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.[4] 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[edit]

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.[5] 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.[5] 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.[5]

Cationic cys-loop receptors[edit]

Type Class IUPHAR-recommended
protein name [6]
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

Anionic cys-loop receptors[edit]

Type Class IUPHAR-recommended
protein name[6]
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[7]
Glycine
(GlyR)
alpha α1
α2
α3
α4
GLRA1
GLRA2
GLRA3
GLRA4
STHE

beta β GLRB

Ionotropic glutamate receptors[edit]

The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2

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 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.

Type Class IUPHAR-recommended
protein name [6]
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

AMPA receptor[edit]

The AMPA receptor bound to a glutamate antagonist showing the amino terminal, ligand binding, and transmembrane domain, PDB 3KG2

The α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (also known as AMPA receptor, or quisqualate receptor) is a non-NMDA-type ionotropic transmembrane receptor for glutamate that mediates fast synaptic transmission in the central nervous system (CNS). 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.[8] AMPARs are found in many parts of the brain and are the most commonly found receptor in the nervous system. The AMPA receptor GluA2 (GluR2) tetramer was the first glutamate receptor ion channel to be crystallized.

AMPA receptor trafficking


Ligands:

NMDA receptors[edit]

Stylized depiction of an activated NMDAR

The N-methyl-D-aspartate receptor (NMDA receptor) is a type of ionotropic glutamate receptor, also a known voltage-gated ion channel. Studies show that it is related to synaptic plasticity and memory.[9][10]
NMDA(N-methyl-D-aspartate) is a type of agonist that could specifically bind to NMDA receptors; it activates the receptor to open the cation channel. It allows Na+ and a small amount of Ca2+ to flow into the cell, which rises the potential. Thus, it is an excitatory receptor. As a voltage-gated ion channel, at resting potentials, most subtypes of NMDA receptor would block by extracellular Mg2+ and Zn2+ , which reduces the synaptic currents. "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".[11]
Ligands:

GABA receptors[edit]

GABA receptors are major inhibitory neurotransmitter expressed in the major interneurons in animal cortex.

GABAA receptor[edit]

GABAA receptor schematic

GABAA receptors are ligand-gated ion channels. GABA (γ-amino butyric acid) being its endogenous ligand, is the major inhibitory neurotransmitter in central nervous system. When activated, it facilitates Cl- flow into the neuron, decrease the potential inside neuron, creating hyperpolarization effect. GABAA receptors occur in all organisms that have a nervous system. To a limited extent the receptors can be found in non-neuronal tissues. Due to their wide distribution within the nervous system of mammals they play a role in virtually all brain functions.

Research shows a series of ligands can specifically bind to GABAA receptor, activate/block the channel. Ligands:

5-HT receptors[edit]

3D structure model of the 5-HT1B receptor in complex with ergotamine based on crystallographic data for PDB 4IAR

5-HT receptors, also known as the serotonin receptors, or 5-hydroxytryptamine receptors, are ligand-gated ion channels. They activate an intracellular second messenger cascade to produce an excitatory/inhibitory response. They are found in mammals, both central nervous system (CNS) and peripheral nervous system (PNS), as well as other animals.[13] Its natural ligand is Serotonin, and it modulate the release of multiple neurotransmitters, such as dopamine, epinephrine/norepinephrine, glutamate, and GABA.
Research confirm that the 5-HT receptors are involved in many neurological processes, such as anxiety, depression, sleep, cognition, memory, and so on. Thus there are several drugs targeting the 5-HT system, including some antidepressants, antipsychotics, anxiolytics, antiemetics, and antimigraine drugs, as well as the psychedelic drugs and empathogens.[14][15][16]

ATP-gated channels[edit]

Figure 1. Schematic representation showing the membrane topology of a typical P2X receptor subunit. First and second transmembrane domains are labeled TM1 and TM2.
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 [6]
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

PIP2-gated channels[edit]

Phosphatidylinositol 4,5-bisphosphate (PIP2) binds to and directly agonizes Inward rectifying potassium channels(Kir).[17] PIP2 is a plasma membrane lipid and its definitive role in gating ion channels was only recently demonstrated by X-ray crystallography.

Indirect modulation[edit]

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[edit]

G-protein-coupled receptor mechanism

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 (e.g. GABAB, NMDA, etc.) are only a part of them.

Table 1. Three major families of Trimeric G Proteins[18]

FAMILY SOME FAMILY MEMBERS ACTION MEDIATED BY FUNCTIONS
I GS α Activate adenylyl cyclase activates Ca2+ channels
Golf α Activates adenylyl cyclase in olfactory sensory neurons
II Gi α Inhibits adenylyl cyclase
βɣ Activates K+ channels
G0 βɣ Activates K+ channels; inactivate Ca2+ channels
α and βɣ Activates phospholipase C-β
Gt (transducin) α Activate cyclic GMP phosphodiesterase in vertebrate rod photoreceptors
III Gq α Activates phospholipase C-β

GABAB receptor[edit]

GABAB receptors 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.[19]

Ligands:

Gα signaling[edit]

The cyclic-adenosine monophosphate (cAMP)-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 (ATP) 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 (PKA) 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 (PLCβ), which catalyzes the cleavage of membrane-bound phosphatidylinositol 4,5-biphosphate (PIP2) into the second messengers inositol (1,4,5) trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on IP3 receptors found in the membrane of the endoplasmic reticulum (ER) 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 (PKC). 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 (CAMKs).

The effectors of the Gα12/13 pathway are three RhoGEFs (p115-RhoGEF, PDZ-RhoGEF, and LARG), 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 (ROCK). Most GPCRs that couple to Gα12/13 also couple to other sub-classes, often Gαq/11.

Gβγ signaling[edit]

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 (GIRKs), P/Q- and N-type voltage-gated Ca2+ channels, as well as some isoforms of AC and PLC, along with some phosphoinositide-3-kinase (PI3K) isoforms.

Clinical relevance[edit]

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.[21][22] In particular, the GABA and NMDA receptors are affected by anaesthetic agents at concentrations similar to those used in clinical anaesthesia.[23]

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.

  • Addiction treatment:

A series recent study shows that GABA receptors are involved with addiction-related behaviors, such as cocaine,[24] heroin, alcohol,[25] etc. Understanding the mechanism of receptors helped scientist develop pharmaceutical tools to treat addictions by modifying the receptors' activity.[26][27]

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,[28] 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.[29]

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,[30][31] study also suggests the efficacy in the treatment of atypical and melancholic depression.[32]

See also[edit]

References[edit]

  1. ^ "ligand-gated channel" at Dorland's Medical Dictionary
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  18. ^ Lodish, Harvey. Molecular cell biology. Macmillan, 2008.
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External links[edit]

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