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Review Article:
John Henstrom Cys-Loop receptors 10/21/15
Encapsulating multiple variations of ligand-gated ion channel receptors, cys-loop receptors include a defining loop formed by a disulfide bond. Within this family of receptors the N-terminal is conserved as well as the three trans membrane domains. The C-terminal varies between the different family members. Each of these subunits has 4 membrane-spanning alpha helices, which play roles in pore formation, binding to the cytoskeleton and more. These receptors are essential in wide variety of neurotransmitter responses as they include many of our excitatory response receptors such as 5-HT/serotonin, GABA, Glycine and nicotinic acetylcholine receptors).
Binding of agonists - When agonists do bind to the receptor (which occurs due to the cys-cys pair on the N-domain) several million cations or anions will cross the membrane per second. These ions are then filtered by the vestibular structure formed in channel by beta sheets. These ions are allowed to enter rapidly due to a series of charged rings in their path that groups hydrated ions together, which leads to charge selectivity. Afterwards, the minute movement of the hydrophobic transmembrane along with the incidents of water filling cause this massive ion influx. - http://www.ncbi.nlm.nih.gov/pubmed/19728176 - Much of what we understand about cys-loop receptors comes from inferences made while studying various examples of this family. For instance, by studying the structures of acetylcholine binding proteins it has been determined that the binding sites are made up of six loops with the first three forming the principal face and then 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 shown repeatedly to be abundant in aromatic residues. - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136689/ - In the example of the binding of serotonin, the relevant group is a 5-hydroxy group which binds to site E129 on loop A. It has been determined that this site is dependent on hydrogen bond acceptor ability. Along with this bonding to E129, a network of coupled noncovalent interactions reach from the TrpB cation all the way to loop A on the proximal side chain E129. While studying anion-selective receptors such as GABA and glycine receptors, it has been shown that the specificity of position of the agonists in the binding site is variable. - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136689/
Opening of Ion channel - 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 angstroms) 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 twist of the whole pentameric receptor. This second method results in minimal rotation of M2. - http://www.ncbi.nlm.nih.gov/pubmed/19444220
Binding of antagonists - Although these have not been studied extensively in literature to date, we are aware of certain examples of the binding of antagonists to the cys-loop receptor family. Antagonists to the 5HT3 receptors have been shown to control symptoms such as nausea and vomiting. These were studied through fluorination techniques which demonstrated that antagonists display a conserved ligand binding mode when exhibiting a cation-pi interaction with TrpB in the 5-HT3A receptor. It was shown through analogues that hydrogen bond acceptor ability at the E129 site on loop A in the 5-HT3A receptor is crucial to binding the necessary ligands. - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136689/ - Despite the recent progress being made in understanding the binding of antagonists to cys-loop receptors, the results from certain receptor reactions cannot be applied to the group as a whole.
Sub-groups (5-HT/serotonin, GABA, Glycine, Nicotinic acetylcholine, Zinc-activated) - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136689/
What is lacking? I need to expand, but should I go into detail about each sub-type? or just more on the main group category?