The Cys-loop
ligand-gated ion channel superfamily is composed of
nicotinic acetylcholine
Nicotinic acetylcholine receptors, or nAChRs, are receptor polypeptides that respond to the neurotransmitter acetylcholine. Nicotinic receptors also respond to drugs such as the agonist nicotine. They are found in the central and peripheral ner ...
,
GABAA,
GABAA-ρ,
glycine,
5-HT3, and
zinc-activated (ZAC)
receptors. These receptors are composed of five
protein subunit
In structural biology, a protein subunit is a polypeptide chain or single protein molecule that assembles (or "''coassembles''") with others to form a protein complex.
Large assemblies of proteins such as viruses often use a small number of ty ...
s which form a pentameric arrangement around a central pore. There are usually 2 alpha subunits and 3 other beta, gamma, or delta subunits (some consist of 5 alpha subunits).
The name of the family refers to a characteristic loop formed by 13 highly conserved
amino acids between two
cysteine (Cys) residues, which form a
disulfide bond near the N-terminal extracellular domain.
Cys-loop receptors are known only in
eukaryotes, but are part of a larger family of pentameric ligand-gated ion channels. Only the Cys-loop clade includes the pair of bridging cysteine residues.
The larger superfamily includes bacterial (e.g.
GLIC The GLIC receptor is a bacterial ( Gloeobacter) Ligand-gated Ion Channel, homolog to the nicotinic acetylcholine receptors. It is a proton-gated (the channel opens when it binds a proton, ion), cation-selective channel (it selectively lets the pos ...
) as well as non-Cys-loop eukaryotic receptors, and is referred to as "pentameric ligand-gated ion channels", or "Pro-loop receptors".
All subunits consist of a large conserved extracellular N-terminal domain, three highly conserved transmembrane domains, a cytoplasmic loop of variable size and amino acid sequence, and a fourth transmembrane region with a relatively short and variable extracellular C-terminal domain.
Neurotransmitter
A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a synapse. The cell receiving the signal, any main body part or target cell, may be another neuron, but could also be a gland or muscle cell.
Neuro ...
s bind at the interface between subunits in the
extracellular domain.
Each subunit contains four membrane-spanning alpha helices (M1, M2, M3, M4). The pore is formed primarily by the M2 helices. The M3-M4 linker is the intracellular domain that binds the cytoskeleton.
Binding
Most knowledge about cys-loop receptors comes from inferences made while studying various members of the family. Research on the structures o
acetylcholine binding proteins(AChBP) determined that the binding sites consist of six loops, with the first three forming the principal face and the next three forming the complementary face. The last loop on the principal face wraps over the ligand in the active receptor. This site is also abundant in
aromatic residues.
Recent literature
indicates that the Trp residue on loop B is crucial for both agonist and antagonist binding. The neurotransmitter is taken into the binding site where it interacts (through
hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-toxic ...
and
cation-π bonding) with the amino acid resides in the aromatic box, located on the principal face of the binding site. Another essential interaction occurs between the agonist and a tyrosine on loop C. Upon interaction, the loop undergoes a conformational change and rotates down to cap the molecule in the binding site.
Channel gating
Through research done on nicotinic acetylcholine receptors it has been determined that the channels are activated through
allosteric interactions between the
binding and gating domains. Once the agonist binds it brings about conformational changes (including moving a beta sheet of the amino-terminal domain, and outward movement from loops 2, F and cys-loop which are tied to the M2-M3 linker and pull the channel open).
Electron microscopy (at 9 Å) shows that the opening is caused by rotation at the M2 domain, but other studies on crystal structures of these receptors has shown that the opening could be a result from a M2 tilt which leads to pore dilation and a quaternary turn of the entire pentameric receptor.
See also
*
Ion channel
Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of io ...
*
Nicotinic agonists
A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine.
Examples include nicotine (by definition), acetylcholine (the endogenous a ...
*
Receptor (biochemistry)
References
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External links
Cys-Loop Ligand Gated Channels
{{Ligand-gated ion channels
Electrophysiology
Ion channels
Ionotropic receptors
Molecular neuroscience
Neurochemistry
Protein families