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 include: Primary endogenous co-agonists: glutamate and either D-serine or glycine Other agonists : aminocyclopropanecarboxylic acid; D-cycloserine; L-aspartate; quinolinate, etc. Partial agonists : N-methyl-D-aspartic acid (NMDA); NRX-1074; 3,5-dibromo-L-phenylalanine, etc. Antagonists: ketamine, PCP, dextropropoxyphene, ketobemidone, tramadol, kynurenic acid (endogenous), etc. 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. 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 trials, study also suggests the efficacy in the treatment of atypical and melancholic depression. See also Action potential Acid-sensing ion channel Calcium-activated potassium channel Cyclic nucleotide-gated ion channel Voltage-dependent calcium channel Receptor (biochemistry) Inositol trisphosphate receptor Metabotropic receptor Ryanodine receptor References External links Ligand-Gated Ion Channel database at European Bioinformatics Institute. Verified availability April 11, 2007. www.esf.edu www.genenames.org www.guidetopharmacology.org Cell biology Electrophysiology Ion channels Ionotropic receptors Membrane biology Molecular neuroscience Neurochemistry Protein families Membrane proteins Transmembrane proteins Transmembrane transporters Transport proteins Integral membrane proteins