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 808154254  45 KHEDSLLKDLFQDYERWVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVP 124
Cdd:cd19018    1 KSEDRLFKHLFQDYQRWVRPVEHLNDTIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYAGITSIRVP 80

                         90       100
                 ....*....|....*....|....*....
gi 808154254 125 SDSVWTPDIVLFDNADGRFEGTSTKTVIR 153
Cdd:cd19018   81 SDSIWIPDIVLYDNADGRFEGTSTKTVVR 109

extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (alpha5), encoded by the CHRNA5 gene, which is part of the CHRNA5/A3/B4 gene cluster. Polymorphisms in this gene cluster have been identified as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. A loss-of-function polymorphism in CHRNA5 is strongly linked to nicotine abuse and schizophrenia; the alpha5 nAChR subunit is strategically situated in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. Alpha5 forms heteropentamers with alpha3beta2 or alpha3beta4 nAChRs which increases the calcium permeability of the resulting receptors possibly playing significant roles in the initiation of ACh-induced signaling cascades under normal and pathological condition. Acetylcholine (ACh) release and signaling via alpha4/beta2 nAChR subunits plays a central role in the control of attention, but a subset of these oligomers also contains alpha5 subunit. A strong association is seen between a CHRNA5 polymorphism and the risk of lung cancer, especially in smokers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  45 KHEDSLLKDLFQDYERWVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVP 124
Cdd:cd19018    1 KSEDRLFKHLFQDYQRWVRPVEHLNDTIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYAGITSIRVP 80

                         90       100
                 ....*....|....*....|....*....
gi 808154254 125 SDSVWTPDIVLFDNADGRFEGTSTKTVIR 153
Cdd:cd19018   81 SDSIWIPDIVLYDNADGRFEGTSTKTVVR 109

Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of Neurotransmitter Receptors TC 1.A.9)Members of the LIC family of ionotropic neurotransmitter receptors are found only in vertebrate and invertebrate animals. They exhibit receptor specificity for (1)acetylcholine, (2) serotonin, (3) glycine, (4) glutamate and (5) g-aminobutyric acid (GABA). All of these receptor channels are probably hetero- orhomopentameric. The best characterized are the nicotinic acetyl-choline receptors which are pentameric channels of a2bgd subunit composition. All subunits arehomologous. The three dimensional structures of the protein complex in both the open and closed configurations have been solved at 0.9 nm resolution.The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine receptors are cationselective while glycine receptors are anion selective). [Transport and binding proteins, Cations and iron carrying compounds]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254   39 EPSSIAKHEDSLLKDLFQDYERWVRPVEHlNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGI 118
Cdd:TIGR00860  23 AKSNLKEVERKLLDELLKNYDARVRPVFG-GPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGV 101

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 808154254  119 KVIRVPSDSVWTPDIVLFDNADGRFEGTSTKTV-IRLLKIGN 159
Cdd:TIGR00860 102 TLVRTPDDSIWVPDIFFYNEKDARFHGITMTNVlVRIHPNGS 143

extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (CHRNA5); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 5 (alpha5), encoded by the CHRNA5 gene, which is part of the CHRNA5/A3/B4 gene cluster. Polymorphisms in this gene cluster have been identified as risk factors for nicotine dependence, lung cancer, chronic obstructive pulmonary disease, alcoholism, and peripheral arterial disease. A loss-of-function polymorphism in CHRNA5 is strongly linked to nicotine abuse and schizophrenia; the alpha5 nAChR subunit is strategically situated in the prefrontal cortex (PFC), where a loss-of-function in this subunit may contribute to cognitive disruptions in both disorders. Alpha5 forms heteropentamers with alpha3beta2 or alpha3beta4 nAChRs which increases the calcium permeability of the resulting receptors possibly playing significant roles in the initiation of ACh-induced signaling cascades under normal and pathological condition. Acetylcholine (ACh) release and signaling via alpha4/beta2 nAChR subunits plays a central role in the control of attention, but a subset of these oligomers also contains alpha5 subunit. A strong association is seen between a CHRNA5 polymorphism and the risk of lung cancer, especially in smokers.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  45 KHEDSLLKDLFQDYERWVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVP 124
Cdd:cd19018    1 KSEDRLFKHLFQDYQRWVRPVEHLNDTIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYAGITSIRVP 80

                         90       100
                 ....*....|....*....|....*....
gi 808154254 125 SDSVWTPDIVLFDNADGRFEGTSTKTVIR 153
Cdd:cd19018   81 SDSIWIPDIVLYDNADGRFEGTSTKTVVR 109

Neurotransmitter-gated ion-channel ligand binding domain; This family is the extracellular ligand binding domain of these ion channels. This domain forms a pentameric arrangement in the known structure.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254   47 EDSLLKDLFQDYERWVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSD 126
Cdd:pfam02931   1 EERLLDDLLSGYDKLVRPVANGSDPVTVSIGLYLQQIIDVDEKNQDLTTNVWLRQTWTDPRLAWNPEDYGGITSLRLPSD 80

                          90       100
                  ....*....|....*....|....*...
gi 808154254  127 SVWTPDIVLFDNADGRFEGTSTKTVIRL 154
Cdd:pfam02931  81 KIWKPDIVLYNKADGIHEVTTPNTNVRV 108

extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (CHRNB3); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 3 (beta3), encoded by the CHRNB3 gene. CHRNB3 polymorphisms have been reported to potentially affect nicotine-induced upregulation of nicotinic and to be associated with disorders such as schizophrenia, autism, and cancer. Beta3 subunit is depleted in the striatum of Parkinson's disease patients. Rare variants in CHRNB3 are also implicated in risk for alcohol and cocaine dependence and independently associated with bipolar disorder. Human alpha6beta2beta3* (* indicating possible additional assembly partners) nAChRs on dopaminergic neurons are important targets for drugs to treat nicotine addiction and Parkinson's disease; (alpha6beta2)(alpha4beta2)beta3 nAChR is essential for addiction to nicotine and a target for drug development for smoking cessation.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVWTPDIVLFDNADGRFEGT-STKT 150
Cdd:cd19026    1 IKVLFGLKISQLVDVDEKNQLMTTNVWLKQEWMDHKLRWNPEDYGGITSIRVPSESLWLPDIVLFENADGRFEGSlMTKA 80

                 ...
gi 808154254 151 VIR 153
Cdd:cd19026   81 IVK 83

extracellular domain of nicotinic acetylcholine receptor; This family contains the extracellular domain of nicotinic acetylcholine receptor (nAChR), a member of the pentameric "Cys-loop" superfamily of transmitter-gated ion channels. nAChR is found in high concentrations at the nerve-muscle synapse, where it mediates fast chemical transmission of electrical signals in response to the endogenous neurotransmitter acetylcholine (ACh) released from the nerve terminal into the synaptic cleft. Thus far, seventeen nAChR subunits have been identified, including ten alpha subunits, four beta subunits, and one gamma, delta, and epsilon subunit each, all found on the cell membrane that non-selectively conducts cations (Na+, K+, Ca++). These nAChR subunits combine in several different ways to form functional nAChR subtypes which are broadly categorized as either muscle subtype located at the neuromuscular junction or neuronal subtype that are found on neurons and on other cell types throughout the body. The muscle type of nAChRs are formed by the alpha1, beta1, gamma, delta, and epsilon subunits while the neuronal type are composed of nine alpha subunits and three beta subunits, which combine in various permutations and combinations to form functional receptors. Among various subtypes of neuronal nAChRs, the homomeric alpha7 and the heteromeric alpha4beta2 receptors are the main subtypes widely distributed in the brain and implicated in the pathophysiology of neurodevelopmental disorders such as schizophrenia and autism and neurodegenerative disorders such as Alzheimer's disease and Parkinson's disease. Among subtypes of muscle nAChRs, the heteromeric subunits (alpha1)2, beta, gamma, and delta in fetal muscle, and the gamma subunit replaced by epsilon in adult muscle have been implicated in congenital myasthenic syndromes and multiple pterygium syndromes due to various mutations. This family also includes alpha- and beta-like nAChRs found in protostomia.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVWTPDIVLFDNADGRFEGT-STKT 150
Cdd:cd18997    1 VNVTFGLTLRQIIDVDEKNQVLTTNVWLRQEWNDERLTWNPSDYGGITSIRVPSDKIWLPDIVLYNNADGDFDSSyKTNV 80

                 ...
gi 808154254 151 VIR 153
Cdd:cd18997   81 IVY 83

extracellular domain of nicotinic acetylcholine receptor subunit alpha 3 (CHRNA3); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 3 (alpha3), encoded by the CHRNA3 gene, and likely plays a role in neurotransmission. The alpha3 subunit is expressed in the aorta and macrophages, and may play a regulatory role in the process of vascular inflammation. One of the most broadly expressed subtype is the alpha3beta4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or presynaptic excitation, mainly by increased Na+ and K+ permeability. The exact pentameric stochiometry of alpha3beta4 receptor is not known and functional assemblies with varying subunit stoichiometries are possible. Alpha4 plays a pivotal role in regulating the inflammatory responses in endothelial cells and macrophages, via mechanisms involving the modulations of multiple cell signaling pathways. Polymorphisms in this gene (CHRNA3) have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  47 EDSLLKDLFQDYERWVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSD 126
Cdd:cd19016    1 EHRLFERLFEDYNEIIRPVANVSDPVIIQFEVSMSQLVKVDEVNQIMETNLWLKHIWNDYKLKWNPSDYGGAEFMRVPAE 80

                         90       100
                 ....*....|....*....|....*...
gi 808154254 127 SVWTPDIVLFDNADGRFE-GTSTKTVIR 153
Cdd:cd19016   81 KIWKPDIVLYNNAVGDFQvDDKTKALLK 108

Cation transporter family protein; The Ligand-gated Ion Channel (LIC) Family of Neurotransmitter Receptors TC 1.A.9)Members of the LIC family of ionotropic neurotransmitter receptors are found only in vertebrate and invertebrate animals. They exhibit receptor specificity for (1)acetylcholine, (2) serotonin, (3) glycine, (4) glutamate and (5) g-aminobutyric acid (GABA). All of these receptor channels are probably hetero- orhomopentameric. The best characterized are the nicotinic acetyl-choline receptors which are pentameric channels of a2bgd subunit composition. All subunits arehomologous. The three dimensional structures of the protein complex in both the open and closed configurations have been solved at 0.9 nm resolution.The channel protein complexes of the LIC family preferentially transport cations or anions depending on the channel (e.g., the acetylcholine receptors are cationselective while glycine receptors are anion selective). [Transport and binding proteins, Cations and iron carrying compounds]

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254   39 EPSSIAKHEDSLLKDLFQDYERWVRPVEHlNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGI 118
Cdd:TIGR00860  23 AKSNLKEVERKLLDELLKNYDARVRPVFG-GPPVTVSFNLFLRSIMDVDEKNMDYTTNIWLRQEWTDERLQWNPEEYPGV 101

                          90       100       110       120
                  ....*....|....*....|....*....|....*....|..
gi 808154254  119 KVIRVPSDSVWTPDIVLFDNADGRFEGTSTKTV-IRLLKIGN 159
Cdd:TIGR00860 102 TLVRTPDDSIWVPDIFFYNEKDARFHGITMTNVlVRIHPNGS 143

extracellular domain of neuronal acetylcholine receptor subunit alpha 9 (CHRNA9); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 9 (alpha9), encoded by the CHRNA9 gene. This protein is involved in cochlea hair cell development and is also expressed in the outer hair cells (OHCs) of the adult cochlea as well as in keratinocytes, the pituitary gland, B-cells, and T-cells. Mammalian alpha9 subunits can form functional homomeric alpha9 receptors as well as the heteromeric alpha9alpha10 receptors, the latter being atypical since the heteromeric alpha9alpha10 receptor is composed only of alpha subunits compared to nAChRs typically assembled from alpha and beta subunits. A stoichiometry of (alpha9)2(alpha10)3 has been determined for the rat recombinant receptor. The alpha9alpha10 nAChR is an important therapeutic target for pain; selective block of alpha9alpha10 nicotinic acetylcholine receptors by the conotoxin RgIA has been shown to be analgesic in an animal model of nerve injury pain, and accelerates recovery of nerve function after injury, possibly through immune/inflammatory-mediated mechanisms. CHRNA9 polymorphisms are associated with non-small cell lung cancer, and effect of a particular SNP (rs73229797) and passive smoking exposure on risk of breast malignancy has been observed.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  50 LLKDLFQDYERWVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVW 129
Cdd:cd19022    4 LFNDLFEDYSNALRPVEDTDKVLNVTLQITLSQIKDMDERNQILTAYLWIRQSWYDAYLKWDRDEYDGLDSIRIPSNLVW 83

                         90       100
                 ....*....|....*....|....*
gi 808154254 130 TPDIVLFDNADGRF-EGTSTKTVIR 153
Cdd:cd19022   84 RPDIVLYNKADDEFsEPVNTNVVLR 108

extracellular domain of neuronal acetylcholine receptor subunit alpha 4 (CHRNA4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 4 (alpha4), encoded by the CHRNA4 gene. Alpha4 forms a functional nAChR by interacting with either nAChR beta2 or beta4 subunits. Alpha4beta2, the major heteropentameric nAChR in the brain, exists in two isoforms, (alpha4)3(beta2)2 and (alpha4)2(beta2)3, with the latter believed to constitute the majority of alpha4beta2 nAChR in the cortex. Both isoforms contain two canonical alpha4:beta2 ACh-binding sites with either low or high ACh sensitivity. This protein is an integral membrane receptor subunit that can interact with either nAChR beta-2 or nAChR beta-4 to form a functional receptor. Mutations in this gene (CHRNA4) cause nocturnal frontal lobe epilepsy type 1. Polymorphisms in this gene may provide protection against nicotine addiction.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 808154254  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVWTPDIVLFDNADGRFEGT 146
Cdd:cd19017    1 VLVRFGLSIAQLIDVDEKNQMMTTNVWVKQEWHDYKLRWDPADYENVTSIRIPSELIWRPDIVLYNNADGDFAVT 75

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 808154254  74 IKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVWTPDIVLFDNADGRFEgTSTKTVIR 153
Cdd:cd03558    3 VTVNISLAQLISVDEVNMDYTTNVFLRQSWIDKRLAYSPADYGGVDSLRLPSEQIWLPDLVFYNNKDADFV-TTDNVLIR 81

                 ....*.
gi 808154254 154 LLKIGN 159
Cdd:cd03558   82 LSPDGT 87

extracellular domain of nicotinic acetylcholine receptor subunit delta (CHRND); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit delta (delta), encoded by the CHRND gene and found in the muscle. Delta nAChR subunit forms a heteropentamer with either (alpha1)2, beta and gamma subunits in embryonic type or (alpha1)2, beta and epsilon subunits in adult type receptors. Defects in this gene are a cause of multiple pterygium syndrome lethal type (MUPSL), congenital myasthenic syndrome slow-channel type (SCCMS), and congenital myasthenic syndrome fast-channel type (FCCMS). The slow-channel congenital myasthenic syndromes (SCCMS) are caused by prolonged opening episodes of AChR due to dominant gain-of-function mutations in the transmembrane regions of the heteropentamer. These mutations produce an increase in the channel opening rate, a decrease in the channel closing rate, or an increase in the affinity of ACh for the AChR, resulting in the stabilization of the open state or the destabilization of the closed state of the AChR.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  50 LLKDLFQD--YERWVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDS 127
Cdd:cd19028    3 LINHLFIErgYNKELRPVAHKDEVVNVALALTLSNLISLKEVDETLTTNVWVEHGWYDHRLTWNASEYGNISILRLPPEM 82

                         90
                 ....*....|....*..
gi 808154254 128 VWTPDIVLFDNADGRFE 144
Cdd:cd19028   83 VWLPEIVLENNNDGQFE 99

extracellular domain (LBD) of cationic Cys-loop neurotransmitter-gated ion channels; This superfamily contains the extracellular domain (ECD) of cationic Cys-loop neurotransmitter-gated ion channels, which include nicotinic acetylcholine receptor (nAChR), serotonin 5-hydroxytryptamine receptor (5-HT3), and zinc-activated ligand-gated ion channel (ZAC) receptor. 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. 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. ZAC forms an ion channel gated by Zn2+, Cu2+, and H+ and is non-selectively permeable to monovalent cations. However, the role of ZAC in Zn2+, Cu2+, and H+ signaling require is as yet unknown.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVWTPDIVLFDNADGRFEGTSTKTV 151
Cdd:cd18989    1 VNVNVSFSLYSILDLDEVEQTLTLSGWLTLTWTDERLTWNPSDYGGITSIVVPSSEIWTPDIVLYNSVDSLDLLGDSNTL 80

                 ...
gi 808154254 152 IRL 154
Cdd:cd18989   81 VRV 83

extracellular domain of nicotinic acetylcholine receptor subunit gamma (CHRNG); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit gamma (gamma), encoded by the CHRNG gene expressed during early fetal development, and replaced by the epsilon subunit in the adult. The gamma subunit forms a heteropentamer with (alpha1)2, beta, and delta and plays a role in neuromuscular organogenesis and ligand binding. Disruption of gamma subunit expression prevents the correct localization of the receptor in cell membranes. Mutations in CHRNG may cause the non-lethal Escobar variant (EVMPS) and lethal form (LMPS) of multiple pterygium syndrome (MPS), a condition characterized by prenatal growth failure with pterygium and akinesia leading to muscle weakness and severe congenital contractures, as well as scoliosis. Muscle-type acetylcholine receptor is the major antigen in the autoimmune disease myasthenia gravis.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 808154254  70 DKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVWTPDIVLFDNADGRFE 144
Cdd:cd19029    1 DVVDVTLKLTLTNLISLNEKEEALTTNVWIEIQWNDYRLRWNPSEYEGIWVLRVPSTMVWLPDIVLENNIDGQFE 75

extracellular domain of serotonin 5-hydroxytryptamine receptor (5-HT3) receptor subunit A (5HT3A); This subfamily contains extracellular domain of subunit A of serotonin 5-HT3 receptor (5-HT3AR), encoded by the HTR3A gene. 5-HT3A subunit forms a homopentameric complex or a heterologous combination with other subunits (B-E). Heteromeric combination of A and B subunits provides the full functional features of this receptor, since either subunit alone results in receptors with very low conductance and response amplitude. 5-HT3A receptors are located in the dorsal vagal complex of the brainstem and in the gastrointestinal (GI) tract, and form a channel circuit that controls gut motility, secretion, visceral perception, and the emesis reflex. These receptors are implicated in several GI and psychiatric disorder conditions including anxiety, depression, bipolar disorder, and irritable bowel syndrome (IBS). Several 5-HT3AR antagonists, such as the isoquinoline Palonosetron, are in clinical use to control emetic reflexes associated with gastrointestinal pathologies and cancer therapies. SNPs in the 5-HT3A serotonin receptor gene are associated with psychiatric disorders.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 808154254  50 LLKDLFQDYERWVRPVEHLNDKIKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVW 129
Cdd:cd19011    4 LSDHLLEGYKKGVRPVRDWRKPTTVSIDVMVYAILNVDEKNQVLTTYIWYRQYWTDEFLQWNPEDFDNVTQLSIPTDSIW 83

                 ....*.
gi 808154254 130 TPDIVL 135
Cdd:cd19011   84 VPDILI 89

extracellular domain of nicotinic acetylcholine receptor subunit epsilon (CHRNE); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit epsilon (epsilon), encoded by the CHRNE gene and found in adult skeletal muscle. Epsilon subunit forms a heteropentamer with (alpha1)2, beta and delta after birth, replacing the gamma subunit seen in embryonic receptors. The adult-type epsilon-AChR has a higher conductance and a shorter open time compared to embryonic gamma-AChR and the open channel is non-selectively cation permeable. Mutations of the CHRNE gene are the most common causes of congenital myasthenic syndrome (CMS), most of which are autosomal recessive loss-of-function mutations, resulting in endplate AChR deficiency. A highly fatal fast-channel syndrome is caused by AChR epsilon subunit mutation (Trp to Arg; changing environment from anionic to cationic) at the agonist binding site at the alpha/epsilon interface of the receptor, thus disrupting agonist binding affinity and gating efficiency.

                         10        20        30        40        50        60        70
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|..
gi 808154254  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVWTPDIVLFDNADGRF 143
Cdd:cd19030    1 VTISLKVTLTNLISLNEKEETLTTSVWIGIDWQDYRLNYSKDDFGGVETLRVPSELVWLPEIVLENNIDGQF 72

acetylcholine binding protein (AChBP); This family contains acetylcholine binding protein (AChBP) which is a soluble extracellular domain homolog secreted by protostomia, and has been widely recognized as a surrogate for the ligand binding domain of nicotinic acetylcholine receptors (nAChRs). AChBP forms a pentameric structure where the interfaces between the subunits provide an acetylcholine (ACh) binding pocket homologous to the binding pocket of nAChRs. Thus far, AChBPs have been characterized only in aquatic mollusks, which have shown low sensitivity to neonicotinoids, the insecticides targeting insect nAChRs. Lymnaea stagnalis acetylcholine binding protein (Ls-AChBP) which has been found in glial cells as a water-soluble protein modulating synaptic ACh concentration has its the binding pocket show better resemblance as it contains all the five aromatic residues fully conserved in nAChR. Five AChBP subunits have been characterized in Pardosa pseudoannulata, a predator enemy against rice insect pests, and share higher sequence similarities with nAChR subunits of both insects and mammals compared with mollusk AChBP subunits.

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gi 808154254  72 IKIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYGGIKVIRVPSDSVWTPDIVLFDNAD 140
Cdd:cd18995    1 VKVSLSLTLQDILSVDEETNEVDLVGWLQMTWKDPRLTWDPAEYGNLKNLRLPSSKIWTPDIAVYNSIG 69

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.

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gi 808154254  74 IKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNPDDYggIKVIRVPS---DSVWTPDIvLFDNA-DGRFEGTSTK 149
Cdd:cd18987    3 VKVSIYIESISSIDEQTMDFTVDMYLRQRWTDPRLAYPDRNG--TDPILLPSdkfDKIWLPDL-YFRNEkSSSFHDVTTP 79

                 ..
gi 808154254 150 TV 151
Cdd:cd18987   80 NV 81

glutamate-gated chloride channel (GluCl) extracellular domain; This subfamily contains extracellular domain of glutamate-gated chloride channel (GluCl) found only in protostomia, but are closely related to mammalian glycine receptors. They have several roles in these invertebrates, including controlling locomotion and feeding, and mediating sensory inputs into behavior. Comparison of the GluCl gene families between organisms shows that insect gene family is relatively simple, while that found in nematodes tends to be larger and more diverse. Glutamate is an inhibitory neurotransmitter that shapes the responses of projection neurons to olfactory stimuli in the Drosophila. GluCls are targeted by the macrocyclic lactone family of anthelmintics and pesticides in arthropods and nematodes, thus making the GluCls of considerable medical and economic importance. In Drosophila melanogaster, GluCl mediates sensitivity to the antiparasitic agents ivermectin and nodulisporic acid, suggesting that their drug target is the same throughout the Ecdysozoa.

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gi 808154254  73 KIKFGLAISQLVDVDEKNQLMTTNVWLKQEWIDVKLRWNpDDYGGIKVIRVPSDS-VWTPDI 133
Cdd:cd18993    3 IVKVNIYVRSISKIDDVKMEYSVQLTFRQEWYDPRLRYD-DTGGKPEYLTLTDDSkIWKPDT 63

extracellular domain of glycine receptor alpha subunit; This subfamily contains extracellular domain of glycine receptor (GlyR or GLR) alpha subunits of the amino acid neurotransmitter glycine. GlyR has four known isoforms of alpha-subunit (alpha1-4, encoded by GLRA1, GLRA2, GLRA3, GLRA4) that are essential to bind ligands, and, along with the GlyR beta subunit, have been described to have a regionally and temporally controlled expression during development and maturation of the central nervous system (CNS). These alpha subunits are highly homologous, but differ in their kinetic properties, temporal and regional expression and physiological functions. They can form functional chloride-permeable GlyR ion channels by forming homopentamers with 5 alpha subunits or heteropentamers with a combination of alpha and beta subunits, either a 2alpha-3beta or 3alpha-2beta stoichiometry. In human, mutations in glycine receptor alpha subunits cause disruption of GlyR surface expression or reduced ability of expressed GlyRs to conduct chloride ions. Mutations in GlyR alpha1 subunit leads to hyperekplexia, a rare neurological disorder characterized by neonatal hypertonia and exaggerated startle responses to unexpected stimuli, while mutations in GlyR alpha2 are known to cause cortical neuronal migration/autism spectrum disorder and in GlyR alpha3 to cause inflammatory pain sensitization/rhythmic breathing. GlyR alpha1 and alpha2 subunits have an important role in regulation of the excitatory-inhibitory balance, control of motor actions, modulation of sedative ethanol effects and probably regulation ethanol preference and consumption.

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gi 808154254  96 NVWLKQEWIDVKLRWN--PDDYGGIKvirvPS--DSVWTPDIVLFDNADGRF-EGTSTKTVIRLLKIGN 159
Cdd:cd19009   26 NIFLRQQWNDPRLAYSeyPDDSLDLD----PSmlDSIWKPDLFFANEKGANFhEVTTDNKLLRISKNGN 90