extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels (also known as ligand-gated ion channel (LGIC)); This superfamily contains the extracellular domain (ECD) of Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), type-A gamma-aminobutyric acid receptor (GABAAR) and glycine receptor (GlyR). These ligand-gated ion channels (LGICs) are found across metazoans and have close homologs in bacteria. They are vital for communication throughout the nervous system. GABAAR and GlyR are anionic channels, both mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. nAChR is a non-selective cation channel that is permeable to Na+ and K+, and some subunit combinations are also permeable to Ca2+. Na+ enters and K+ exits to allow net flow of positively charged ions inward. 5-HT3, a cation-selective channel, binds serotonin and is permeable to Na+, K+, and Ca2+. It mediates neuronal depolarization and excitation within the central and peripheral nervous systems. These ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on the inhibitory half of the Cys-loop receptor family. The ECD contains the ligand binding sites for these receptors.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392925213  61 ELSTEGFFEMSWTNTTLDFTNLNaCHKTVRIKSLLHI-FWLPHVYFP---FSYNLEESRNLYNIEIHESGNITLSKRLKQ 136
Cdd:cd18987   21 DFTVDMYLRQRWTDPRLAYPDRN-GTDPILLPSDKFDkIWLPDLYFRnekSSSFHDVTTPNVLVRIFPNGTVLYSQRLTL 99

                         90       100
                 ....*....|....*....|....*....
gi 392925213 137 SIPCKEQSDSHPFSNNTCTL---SWKYTN 162
Cdd:cd18987  100 TLSCPMNLQKFPFDTQVCTLrleSYGYTT 128

extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels; This family contains the extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels which include type-A gamma-aminobutyric acid receptor (GABAAR), glycine receptor (GlyR), invertebrate glutamate-gated chloride channel (GluCl), and histimine-gated chloride channel (HisCl). These neurotransmitter receptors directly mediate chloride permeability and constitute one half of the Cys-loop receptor family. Receptors in this family are composed of five either identical or homologous subunits, which generate diversity in functional profiles and pharmacological preferences. GABAAR and GlyR, both mediate fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. GluCl channels are found only in protostomia, but are closely related to mammalian glycine receptors (GlyRs). They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. Ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on this inhibitory half of the Cys-loop receptor family. Many of the therapeutically useful compounds acting at Cys-loop receptors target an allosteric site. The sites in Cys-loop receptors at which these allosteric ligands bind and their structure-based mechanisms of action are largely unresolved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392925213  61 ELSTEGFFEMSWTNTTLDFTNLNaCHKTVRIKSLLHI-FWLPHVYFP---FSYNLEESRNLYNIEIHESGNITLSKRLKQ 136
Cdd:cd18987   21 DFTVDMYLRQRWTDPRLAYPDRN-GTDPILLPSDKFDkIWLPDLYFRnekSSSFHDVTTPNVLVRIFPNGTVLYSQRLTL 99

                         90       100
                 ....*....|....*....|....*....
gi 392925213 137 SIPCKEQSDSHPFSNNTCTL---SWKYTN 162
Cdd:cd18987  100 TLSCPMNLQKFPFDTQVCTLrleSYGYTT 128

extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels; This family contains the extracellular domain (ECD) of anionic Cys-loop neurotransmitter-gated ion channels which include type-A gamma-aminobutyric acid receptor (GABAAR), glycine receptor (GlyR), invertebrate glutamate-gated chloride channel (GluCl), and histimine-gated chloride channel (HisCl). These neurotransmitter receptors directly mediate chloride permeability and constitute one half of the Cys-loop receptor family. Receptors in this family are composed of five either identical or homologous subunits, which generate diversity in functional profiles and pharmacological preferences. GABAAR and GlyR, both mediate fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR receptor pore, resulting in hyperpolarization of the neuron. GluCl channels are found only in protostomia, but are closely related to mammalian glycine receptors (GlyRs). They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. Ligand-gated chloride channels are critical not only for maintaining appropriate neuronal activity, but have long been important therapeutic targets: benzodiazepines, barbiturates, some intravenous and volatile anaesthetics, alcohol, strychnine, picrotoxin, and ivermectin all derive their biological activity from acting on this inhibitory half of the Cys-loop receptor family. Many of the therapeutically useful compounds acting at Cys-loop receptors target an allosteric site. The sites in Cys-loop receptors at which these allosteric ligands bind and their structure-based mechanisms of action are largely unresolved.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 392925213  61 ELSTEGFFEMSWTNTTLDFTNLNaCHKTVRIKSLLHI-FWLPHVYFP---FSYNLEESRNLYNIEIHESGNITLSKRLKQ 136
Cdd:cd18987   21 DFTVDMYLRQRWTDPRLAYPDRN-GTDPILLPSDKFDkIWLPDLYFRnekSSSFHDVTTPNVLVRIFPNGTVLYSQRLTL 99

                         90       100
                 ....*....|....*....|....*....
gi 392925213 137 SIPCKEQSDSHPFSNNTCTL---SWKYTN 162
Cdd:cd18987  100 TLSCPMNLQKFPFDTQVCTLrleSYGYTT 128