Whereas the voltage-gated ion channels underlying the action potential typically allow only one type of ion to permeate, channels activated by extracellular ligands are usually less selective, allowing two or more types of ions to pass through the channel pore[1]. In most cases, these ligand gated ion channels have allosteric binding sites, and can be regulated by endogenous chemical signals originating from neurotransmitters and/or cytoplasmic modulators. Ligand gated ions channels (LGICs) can be classified in three superfamilies. The superfamily of Cys-loop receptors resembles the structure and mechanism of the nicotinic acetylcholine receptors, and all share a characteristic loop formed by a disulfide bond between two cysteine residues in the N terminal extracellular domain. Most conspicuously, all the receptors of this superfamily possess four hydrophobic amino-acid sequences, which are long enough to span the plasma membrane. Accordingly, they sometimes are termed four-transmembrane (4TM)-sequence receptors. This first class of LGICs includes both anionic receptors (glycine (GlyR), GABAA (GABAAR), as well as cationic receptors (nicotinic acetylcholine (nAChR), Zinc-activated ion channel (ZAC), and one class of serotonin receptors (5-HT3)). Secondly, the superfamily of ionotropic glutamate receptors (iGluR) share the feature of being activated by the neurotransmitter glutamate. They form tetramers with each subunit consisting of three domains. The one domain consisting of three transmembrane helices (TMD) actually forms the ions channel. The members of this superfamily are AMPA (GluA), Kainate (GluK), NMDA (GluN), and orphan (GluD) receptors. Finally, the third superfamily of LGICs is represented by a class of ATP-gated channels. The only members known to date are the P2X receptors (P2X 1-7) which form trimers with only two transmembrane helices per subunit[2].