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 530406617    3 EADISGYIPNGEWDLVGIPGKRSErFYECCKEPYPDVTFTVTMRRRTLYYGLNLLIPCVLISALALLVFLLPAD-SGEKI 81
Cdd:TIGR00860 195 QVDDSLFISLPEFELLGVYGTRYC-TSETNTGEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADaSGARV 273

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617   82 SLGITVLLSLTVFMLLVAEIMPATSdSVPLIAQYFASTMIIVGLSVVVTVIVLQYHHHDPDGGKmpkwtRVILLNWCAWF 161
Cdd:TIGR00860 274 SLGITTLLTMTTFSSGVRESLPAVS-YVKAIDVYFAVCMAFVFLALLETAFVNYVHHKDPAQGK-----RHLLLERCAWR 347

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617  162 LRMKRPGEDKVRPACQHKQrrcsLASVEMSAVAPPpasngnllyigfRGLDgvhcvptpdsgvvcgrmacSPTHDEHLLH 241
Cdd:TIGR00860 348 LCKQEPGEDYRRPALDHAS----LSSVEMRAKDGG------------RGLE-------------------SPTERQRLLH 392

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 530406617  242 GGQPPEGDPDLAKILEEVRyIANRFRCQDESEAVCSEWKFAACVVDRLCLMAFSVFTIICTIGILMSA 309
Cdd:TIGR00860 393 SPPPAEGDLDLAGILEEVR-IAHRFRKRDESEEVVRDWKFRAKVIDKLSRMAFPLAFLLFNIGYWMSY 459

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 530406617    3 EADISGYIPNGEWDLVGIPGKRSErFYECCKEPYPDVTFTVTMRRRTLYYGLNLLIPCVLISALALLVFLLPAD-SGEKI 81
Cdd:TIGR00860 195 QVDDSLFISLPEFELLGVYGTRYC-TSETNTGEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADaSGARV 273

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617   82 SLGITVLLSLTVFMLLVAEIMPATSdSVPLIAQYFASTMIIVGLSVVVTVIVLQYHHHDPDGGKmpkwtRVILLNWCAWF 161
Cdd:TIGR00860 274 SLGITTLLTMTTFSSGVRESLPAVS-YVKAIDVYFAVCMAFVFLALLETAFVNYVHHKDPAQGK-----RHLLLERCAWR 347

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617  162 LRMKRPGEDKVRPACQHKQrrcsLASVEMSAVAPPpasngnllyigfRGLDgvhcvptpdsgvvcgrmacSPTHDEHLLH 241
Cdd:TIGR00860 348 LCKQEPGEDYRRPALDHAS----LSSVEMRAKDGG------------RGLE-------------------SPTERQRLLH 392

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 530406617  242 GGQPPEGDPDLAKILEEVRyIANRFRCQDESEAVCSEWKFAACVVDRLCLMAFSVFTIICTIGILMSA 309
Cdd:TIGR00860 393 SPPPAEGDLDLAGILEEVR-IAHRFRKRDESEEVVRDWKFRAKVIDKLSRMAFPLAFLLFNIGYWMSY 459

transmembrane domain of Cys-loop neurotransmitter-gated ion channels, includes 5HT3, nAChR, and ZAC; This superfamily contains the transmembrane (TM) domain 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. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The ligand-gated ion channels (LGICs) in this family 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 530406617  50 LYYGLNLLIPCVLISALALLVFLLPADSGEKISLGITVLLSLTVFMLLVAEIMPATSDSVPLIAQYFASTMIIVGLSVVV 129
Cdd:cd19051    1 LFYVFNLILPCVLLSVLALLVFLLPPDSGEKVSLGITVLLSLTVFLLLVSESLPPTSDSVPLIGIYLLATMVLSALSTVL 80

                 ....*....
gi 530406617 130 TVIVLQYHH 138
Cdd:cd19051   81 TVIVLNLHH 89

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 530406617    3 EADISGYIPNGEWDLVGIPGKRSErFYECCKEPYPDVTFTVTMRRRTLYYGLNLLIPCVLISALALLVFLLPAD-SGEKI 81
Cdd:TIGR00860 195 QVDDSLFISLPEFELLGVYGTRYC-TSETNTGEYPCLTFSFVLRRRPLYYLLQLYIPSILIVILSWVSFWLPADaSGARV 273

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617   82 SLGITVLLSLTVFMLLVAEIMPATSdSVPLIAQYFASTMIIVGLSVVVTVIVLQYHHHDPDGGKmpkwtRVILLNWCAWF 161
Cdd:TIGR00860 274 SLGITTLLTMTTFSSGVRESLPAVS-YVKAIDVYFAVCMAFVFLALLETAFVNYVHHKDPAQGK-----RHLLLERCAWR 347

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617  162 LRMKRPGEDKVRPACQHKQrrcsLASVEMSAVAPPpasngnllyigfRGLDgvhcvptpdsgvvcgrmacSPTHDEHLLH 241
Cdd:TIGR00860 348 LCKQEPGEDYRRPALDHAS----LSSVEMRAKDGG------------RGLE-------------------SPTERQRLLH 392

                         250       260       270       280       290       300
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 530406617  242 GGQPPEGDPDLAKILEEVRyIANRFRCQDESEAVCSEWKFAACVVDRLCLMAFSVFTIICTIGILMSA 309
Cdd:TIGR00860 393 SPPPAEGDLDLAGILEEVR-IAHRFRKRDESEEVVRDWKFRAKVIDKLSRMAFPLAFLLFNIGYWMSY 459

transmembrane domain of Cys-loop neurotransmitter-gated ion channels, includes 5HT3, nAChR, and ZAC; This superfamily contains the transmembrane (TM) domain 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. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The ligand-gated ion channels (LGICs) in this family 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 530406617  50 LYYGLNLLIPCVLISALALLVFLLPADSGEKISLGITVLLSLTVFMLLVAEIMPATSDSVPLIAQYFASTMIIVGLSVVV 129
Cdd:cd19051    1 LFYVFNLILPCVLLSVLALLVFLLPPDSGEKVSLGITVLLSLTVFLLLVSESLPPTSDSVPLIGIYLLATMVLSALSTVL 80

                 ....*....
gi 530406617 130 TVIVLQYHH 138
Cdd:cd19051   81 TVIVLNLHH 89

extracellular domain of neuronal acetylcholine receptor subunit alpha 7 (CHRNA7); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 7 (alpha7), encoded by the CHRNA7 gene. Alpha7 subunits form a homo-pentameric channel, displays marked permeability to calcium ions and is a major component of brain nicotinic receptors that are blocked by, and highly sensitive to, alpha-bungarotoxin. This protein is ubiquitously expressed in both the central nervous system and in the periphery, in several tissues, including adrenal, small intestine, testis, and stomach. CHRNA7 is located in a region identified as a major susceptibility locus for juvenile myoclonic epilepsy and a chromosomal location involved in the genetic transmission of schizophrenia. It is also genetically linked to other disorders with cognitive deficits, including bipolar disorder, ADHD, Alzheimer's disease, and Rett syndrome. An evolutionarily recent partial duplication of CHRNA7 on chromosome 15 forms a new gene, CHRFAM7A or FAM7A, which encodes the protein dup-alpha7. This protein assembles with alpha7 subunits, results in fewer binding sites and is a dominant negative regulator of alpha7 nAChR function.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 530406617   1 MQEADISGYIPNGEWDLVGIPGKRSERFYECCKEPYPDVTFTVTMRRR 48
Cdd:cd19020  133 MQEADISGYISNGEWDLVGVPGKRNEKFYECCKEPYPDVTFTVTMRRR 180

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
                 ....*....|....*....|....*....|....*....|....*..
gi 530406617   2 QEADISGYIPNGEWDLVGIPGKRSERFYECCKEPYPDVTFTVTMRRR 48
Cdd:cd18997  135 DTVDLSDYIENGEWDLLGAPAKRNVVKYSCCPEPYPDVTFTIHIRRK 181

transmembrane domain of 5-hydroxytryptamine 3 (5-HT3) receptor; This family contains transmembrane (TM) domain of the serotonin 5-HT3 receptors. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. The 5-HT3 channel is cation-selective and mediates neuronal depolarization and excitation within the central and peripheral nervous systems. Like other ligand gated ion channels, the 5-HT3 receptor consists of five subunits arranged around a central ion conducting pore, which is permeable to Na+, K+, and Ca2+ ions. Binding of the neurotransmitter 5-hydroxytryptamine (serotonin) to the 5-HT3 receptor opens the channel, which then leads to an excitatory response in neurons, and the rapidly activating, desensitizing, inward current is predominantly carried by Na+ and K+ ions. This receptor is most closely related by homology to the nicotinic acetylcholine receptor (nAChR). Five subunits have been identified for this family: 5-HT3A, 5-HT3B, 5-HT3C, 5-HT3D, and 5-HT3E, encoded by HTR3A-E genes. Only 5-HT3A subunits are able to form functional homomeric receptors, whereas the 5-HT3B, C, D, and E subunits form heteromeric receptors with 5-HT3A. Different receptor subtypes are important mediators of nausea and vomiting during chemotherapy, pregnancy, and following surgery, while some contribute to neuro-gastroenterologic disorders such irritable bowel syndrome (IBS) and eating disorders as well as co-morbid psychiatric conditions. 5-HT3 receptor antagonists are established treatments for emesis and IBS, and are beneficial in the treatment of psychiatric diseases.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617  50 LYYGLNLLIPCVLISALALLVFLLPADSGEKISLGITVLLSLTVFMLLVAEIMPATSDSVPLIAQYFASTMIIVGLSVVV 129
Cdd:cd19063    1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATAIGTPLIGVYFVVCLALMVLSLLE 80

                 ....*....
gi 530406617 130 TVIVLQYHH 138
Cdd:cd19063   81 TILIVKLLH 89

transmembrane domain of Cys-loop neurotransmitter-gated ion channels; This superfamily contains the transmembrane domain 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 where the sign of synaptic connections (excitatory or inhibitory) is determined by the charge of the ions that flow through these channels. In general, channels that conduct positive ions are excitatory, whereas channels that conduct negative ions are inhibitory. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. 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.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617  51 YYGLNLLIPCVLISALALLVFLLPADSGEKISLGITVLLSLTVFMLLVAEIMPATSdSVPLIAQYFASTMIIVGLSVVVT 130
Cdd:cd03559    1 YYAVSLLLPSILIMVVSWVGFWLPPDSGERVSFKITLLLTYSVFLIIVSDTLPATP-YTPLIDVYFVVCMALLFIALLET 79

                         90       100
                 ....*....|....*....|....*.
gi 530406617 131 V-IVLQYHHHDPDGGKMPKWTRVILL 155
Cdd:cd03559   80 IfIVRLVHKQDRVGYVIDRLLRRIFP 105

extracellular domain of neuronal acetylcholine receptor subunit alpha 10 (CHRNA10); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 10 (alpha10), encoded by the CHRNA10 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. Unlike alpha9 nAChR subunits, alpha10 subunits do not generate functional channels when expressed heterologously, suggesting that alpha10 might serve as a structural subunit, much like a beta subunit of heteromeric receptors, providing only complementary components to the agonist binding site. Mammalian alpha10 subunits can form functional heteromeric alpha9alpha10 receptors, an atypical heteromeric receptor since it 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.

                         10        20        30        40
                 ....*....|....*....|....*....|....*....|....*...
gi 530406617   1 MQEADISGYIPNGEWDLVGIPGKRSERFYECCKEPYPDVTFTVTMRRR 48
Cdd:cd19023  134 LDTGDLTDFVENVEWEVLGMPAKRNVITYGCCSEPYPDVTYTLLLKRR 181

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
                 ....*....|....*....|....*....|....*....|....*..
gi 530406617   2 QEADISGYIPNGEWDLVGIPGKRSERFYecCKEPYPDVTFTVTMRRR 48
Cdd:cd18989  136 NGVDLEDYEENGEWELLSTSVSREEDKY--CNETYSELTFTITLKRR 180

transmembrane domain of prokaryotic pentameric ligand-gated ion channels (pLGIC); This family contains transmembrane (TM) domain of bacterial pentameric ligand-gated ion channels (pLGICs) including ones from Gloeobacter violaceus (GLIC) and Erwinia chrysanthemi (ELIC). The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. Studies show that GLIC activation is inhibited by most general anaesthetics at clinical concentrations, including xenon which has been used in clinical practice as a potent gaseous anesthetic for decades. Xenon binding sites have been identified in three distinct regions of the TMD: in a large intra-subunit cavity, in the pore, and at the interface between adjacent subunits. Propofol, the drug used for induction and maintenance of general anesthesia, and desflurane, a negative allosteric modulator of GLIC bind at the entrance in the intra-subunit cavity. Alzheimer's drug memantine, which blocks ion conduction at vertebrate pLGICs by plugging the channel pore, has been shown to have similar potency in ELIC.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617  51 YYGLNLLIPCVLISALALLVFLL-PADSGEKISLGITVLLSLTVFMLLVAEIMPATSDSVPLIAQYFAST-MIIVGLSVV 128
Cdd:cd19050    1 YYIWKVILPLLLIVAMSWSVFWIdPESFGPQIGISVTSMLTLIAFNFLISNSLPRLPYLTFMDAFILASYlLVFLALIEV 80

                         90       100
                 ....*....|....*....|....*
gi 530406617 129 VTVIVLQYHHHDPDGGKMPKWTRVI 153
Cdd:cd19050   81 IVTHYLARNGKEALALRIDRISRWA 105

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
                 ....*....|....*....|....*....|....*....|...
gi 530406617   5 DISGYIPNGEWDLVGIPGKRSERFYECCKEPYPDVTFTVTMRR 47
Cdd:cd19016  163 NLKDYWESGEWAIIKAPGYKHDIKYNCCEEIYPDITYSLYIRR 205

transmembrane domain of anionic Cys-loop neurotransmitter-gated ion channels, includes GABAAR, GlyR and GluCl; This family contains transmembrane domain of type-A gamma-aminobutyric acid receptor (GABAAR) as well as glycine receptor (GlyR) subunits. Thus far, there are 18 vertebrate receptor subunits categorized in 7 families: alpha1-6, beta1-4, gamma1-4, delta, epsilon, theta, rho, and pi. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. GlyR, with a similar structure as GABAAR, is concentrated in the brain stem and spinal cord in the CNS and can be activated by glycine, beta-alanine, or taurine. It is selectively blocked by the high-affinity competitive antagonist strychnine, which causes death by asphyxiation. An autosomal dominant R271Q mutation in GLRA1 causes hyperekplexia (Startle disease or Stiff Baby Syndrome) by decreasing glycine sensitivity.

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 530406617  51 YYGLNLLIPCVLISALALLVFLLPADS-GEKISLGITVLLSLTVFMLLVAEIMPATS-----DSvpliaqYFASTMIIVG 124
Cdd:cd19049    1 YYLIQTYIPSILIVILSWVSFWIDPEAvPARVSLGITTVLTMTTQSSGVRSSLPKVSyvkaiDV------WLGVCFVFVF 74

                         90       100
                 ....*....|....*....|....*....
gi 530406617 125 LSVVVTVIVLQYHHHdpdggKMPKWTRVI 153
Cdd:cd19049   75 AALLEYAVVNYLKAS-----KIDRISRIL 98

transmembrane domain of beta subunits of type-A gamma-aminobutyric acid receptor (GABAAR); This family contains transmembrane (TM) domain of the beta subunit of type-A beta-aminobutyric acid receptor (GABAAR), which includes beta1-beta4 in vertebrates. The transmembrane region consists of four transmembrane-spanning alpha-helical segments (M1-M4) that are linked by loops. The intracellular loop that links M1 and M2 determines the ion selectivity of the channel. GABAAR is an anionic channel, mediating fast inhibitory synaptic transmission. Cl- ions are selectively conducted through the GABAAR pore, resulting in hyperpolarization of the neuron. GABAAR is the principal mediator of rapid inhibitory synaptic transmission in the human brain. A decline in GABAAR signaling triggers hyperactive neurological disorders such as insomnia, anxiety, and epilepsy. Mutations or genetic variations of the genes encoding beta2 (GABRB2) and beta3 (GABRB3) have been associated with human epilepsy, both with and without febrile seizures. Mutations in GABRB2, and GABRB3 have been associated with infantile spasms and Lennox-Gastaut syndrome. A de novo missense mutation of GABRB2 causes early myoclonic encephalopathy, a disease with a devastating prognosis, characterized by neonatal onset of seizures. Another de novo heterozygous missense variant in exon 4 of GABRB2 is associated with intellectual disability and epilepsy. Mutations in the GABRB1 gene encoding beta1 promote alcohol consumption through increased tonic inhibition.

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gi 530406617  51 YYGLNLLIPCVLISALALLVFLLPAD-SGEKISLGITVLLSLTVFMLLVAEIMPatsdSVPLIAqyfASTMIIVGLSVVV 129
Cdd:cd19053    1 YFILQTYMPSILITILSWVSFWINYDaSAARVALGITTVLTMTTINTHLRETLP----KIPYVK---AIDMYLMGCFVFV 73

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gi 530406617 130 TVIVLQYHHHD-PDGGKMPKWTRVIL 154
Cdd:cd19053   74 FLALLEYAFVNyIDVNAIDRWSRIIF 99

extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (CHRNB4); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta 4 (beta4), encoded by the CHRNB4 gene and ubiquitously expressed on lung epithelial cells. The cluster of human neuronal nicotinic receptor gene CHRNA5-CHRNA3-CHRNB4 is related to drug-related behaviors and the development of lung cancer. One of the most broadly expressed subtype is the alpha-3 beta-4 nAChR, also known as the ganglion-type nicotinic receptor, located in the autonomic ganglia and adrenal medulla, where activation yields post- and/or pre-synaptic excitation, mainly by increased Na+ and K+ permeability. Beta4 forms heteromeric nAchRs to modulate receptor affinity for nicotine, but the exact pentameric stochiometry of alpha3beta4 receptor is not known; functional assemblies with varying subunit stoichiometries are possible.

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gi 530406617   4 ADISGYIPNGEWDLVGIPGKRSerfyECCKEP-YPDVTFTVTMRRR 48
Cdd:cd19027  137 ASMDDFTPSGEWDIVALPGRRT----VNPLDPtYVDVTYDFIIKRK 178

extracellular domain of nicotinic acetylcholine receptor subunit beta-like found in protostomia; This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit beta-like in organisms that include arthropods, mollusks, annelid worms, and flat worms, and have their cholinergic system limited to the central nervous system. C. elegans genome encodes 29 acetylcholine receptor subunits, of which the levamisole-sensitive receptor alpha-subunits (L-AChR), UNC-38, UNC-63, and LEV-8, form heteromers with the two non-alpha (also known as beta-like) subunits, UNC-29 and LEV-1 found in this subfamily. This receptor functions as the main excitatory postsynaptic receptor at neuromuscular junctions, indicating that many are expressed in neurons. In insects, the receptors supply fast synaptic excitatory transmission and represent a major target for several insecticides. In Drosophila, ten exclusively neuronal nAChR subunits have been identified, Dalpha1-Dalpha7 and Dbeta1-Dbeta3, and various combinations of these subunits and mutations are key to nAChR function. Dbeta1 subunits in dopaminergic neurons play a role in acute locomotor hyperactivity caused by nicotine in male Drosophila. Mutations of Dbeta2 or Dalpha1 nAChR subunits in Drosophila strains have significantly lower neonicotinoid-stimulated release, but no changes in nicotine-stimulated release; they are highly resistant to the neonicotinoids nitenpyram and imidacloprid. This family also includes a novel nAChR found in Aplysia bag cell neurons (neuroendocrine cells that control reproduction) which is a cholinergic ionotropic receptor that is both, nicotine insensitive and acetylcholine sensitive.

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gi 530406617   2 QEADISGYIPNGEWDLVGIPGKRSErfYECCKEPYPDVTFTVTMRRRT 49
Cdd:cd19032  163 KFVDLSDYWKSGTWDIIDVPGQLVN--KDDAGPTETDIIFKIKIRRKT 208