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 966965633    1 MKFGSWTY--DKAKIDLVNMHS-RVDQLDFWESGEWVIVDAVGTyNTRKYECCAEIYPDITYAFVIRRLPLFYTINLIIP 77
Cdd:TIGR00860 172 LKFESWGYttNDIKLEWKEQGAvQVDDSLFISLPEFELLGVYGT-RYCTSETNTGEYPCLTFSFVLRRRPLYYLLQLYIP 250

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633   78 CLLISCLTVLVFYLPSEC-GEKITLCISVLLSLTVFLLLITEIIPSTSlVIPLIGEYLLFTMIFVTLSIVITVFVLNVHH 156
Cdd:TIGR00860 251 SILIVILSWVSFWLPADAsGARVSLGITTLLTMTTFSSGVRESLPAVS-YVKAIDVYFAVCMAFVFLALLETAFVNYVHH 329

                         170       180       190       200       210       220       230       240
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  157 RSPRTHTmpawvRRVFLDIVPRLLLMKRPSvvkDNCRRLIESMHKMASA-PRFWPEPEGEPAATSGTQSRHPPSPSCVPL 235
Cdd:TIGR00860 330 KDPAQGK-----RHLLLERCAWRLCKQEPG---EDYRRPALDHASLSSVeMRAKDGGRGLESPTERQRLLHSPPPAEGDL 401

                  ..
gi 966965633  236 DV 237
Cdd:TIGR00860 402 DL 403

transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). 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. 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 966965633  68 LFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19064    1 LFYTVNLIIPCVLISFLTVLVFYLPADSGEKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSIIV 80

                         90
                 ....*....|
gi 966965633 148 TVFVLNVHHR 157
Cdd:cd19064   81 TVIVLNVHHR 90

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRRL 66
Cdd:cd19017  116 MKFGSWTYDKAKIDLVSMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFIIRRL 181

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  210 PEPEGEPAATSGTQSRHPPS------------PSCVPLDVPAESGPACKSPSDQlPALQPPEAEKASPHPSPGPYRPPHS 277
Cdd:PHA03247 2754 PARPARPPTTAGPPAPAPPAapaagpprrltrPAVASLSESRESLPSPWDPADP-PAAVLAPAAALPPAASPAGPLPPPT 2832

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  278 TQAPGLAKARSLSVQHMSSPGEAVEGGVRCRSRSIQYCVPRDNAA---PEADVQAAGALaSRKTHSAELPPpDQPSPRKC 354
Cdd:PHA03247 2833 SAQPTAPPPPPGPPPPSLPLGGSVAPGGDVRRRPPSRSPAAKPAAparPPVRRLARPAV-SRSTESFALPP-DQPERPPQ 2910

                         170       180
                  ....*....|....*....|....
gi 966965633  355 TCGKEPPSVSPSATLKARSTKAPP 378
Cdd:PHA03247 2911 PQAPPPPQPQPQPPPPPQPQPPPP 2934

transmembrane domain of nicotinic acetylcholine receptor (nAChR); This family contains transmembrane (TM) domain of the nicotinic acetylcholine receptor (nAChR). 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. 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 966965633  68 LFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19064    1 LFYTVNLIIPCVLISFLTVLVFYLPADSGEKITLSISVLLALTVFLLLIAEIIPPTSLVVPLIGKYLLFTMILVTLSIIV 80

                         90
                 ....*....|
gi 966965633 148 TVFVLNVHHR 157
Cdd:cd19064   81 TVIVLNVHHR 90

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRRL 66
Cdd:cd19017  116 MKFGSWTYDKAKIDLVSMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFIIRRL 181

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 966965633  68 LFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19051    1 LFYVFNLILPCVLLSVLALLVFLLPPDSGEKVSLGITVLLSLTVFLLLVSESLPPTSDSVPLIGIYLLATMVLSALSTVL 80

                         90       100
                 ....*....|....*....|....*.
gi 966965633 148 TVFVLNVHHRSPRthtMPAWVRRVFL 173
Cdd:cd19051   81 TVIVLNLHHVLDR---LFFWLFLLVT 103

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRR 65
Cdd:cd18997  116 LKFGSWTYDGSELDLQLKSDTVDLSDYIENGEWDLLGAPAKRNVVKYSCCPEPYPDVTFTIHIRR 180

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYEccAEIYPDITYAFVIRRL 66
Cdd:cd03558  116 MKLESWTYDTTDIELVWDSERPDQADFLELPEWDIVEKRGRYCTVVYN--TGIYSDITYRFRLKRQ 179

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCaeIYPDITYAFVIRRLPL 68
Cdd:cd19018  142 MKFGSWTYDGSQVDIILEDYDVDKRDFFDNGEWEIVSATGSKGNRTDGCC--WYPFITYSFIIRRLPL 207

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*.
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAeiYPDITYAFVIRRL 66
Cdd:cd19026  116 MKFGSWTYDGNMVDLILIDENVDRKDFFDNGEWEILNAKGMKGNRKDGLYS--YPFITYSFVLRRL 179

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        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRR 65
Cdd:cd19023  116 LTFGSWTYNGNQIDILNLLDTGDLTDFVENVEWEVLGMPAKRNVITYGCCSEPYPDVTYTLLLKR 180

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
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYecCAEIYPDITYAFVIRR 65
Cdd:cd18989  117 LRFGSWSYTTDEINLTPSSNGVDLEDYEENGEWELLSTSVSREEDKY--CNETYSELTFTITLKR 179

extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (CHRNA1); This subfamily contains the extracellular domain of nicotinic acetylcholine receptor subunit alpha 1 (alpha1), encoded by the CHRNA1 gene. These muscle type nicotinic subunits form heteropentamers with other nAChR subunits, most broadly expressed as combination of two alpha1, beta1, delta, and epsilon subunits in mature muscles, and of two alpha1, beta1, delta, and gamma in embryonic cells. The alpha1 subunit in human nAChR is the primary target of Myasthenia gravis antibodies that disrupt communication between the nervous system and the muscle, causing chronic muscle weakness.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*...
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDQLDFWESGEWVIVDAVGTYNTRKYECCAEI-YPDITYAFVIRRLP 67
Cdd:cd19014  143 MKLGTWTYDGTLVVINPESDRPDLSNFMESGEWVMKDYRGWKHWVYYTCCPDTpYLDITYHFLLQRLP 210

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 966965633  68 LFYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLVIPLIGEYLLFTMIFVTLSIVI 147
Cdd:cd19063    1 LLYVVNLLIPSIFLMLVDLASFYLPPNSGERLGFKVTLLLGYSVFLLILNDLLPATAIGTPLIGVYFVVCLALMVLSLLE 80

                 ....*....
gi 966965633 148 TVFVLNVHH 156
Cdd:cd19063   81 TILIVKLLH 89

extracellular domain of neuronal acetylcholine receptor subunit alpha-7-like; 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.

                         10        20        30        40        50        60
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*
gi 966965633   1 MKFGSWTYDKAKIDLVNMHSRVDqlDFWESGEWVIVDAVGTYNTRKYECCAEIYPDITYAFVIRR 65
Cdd:cd19021  116 LKFGSWTHSGWLIDLQMLEADIS--NYISNGEWDLVGVPGKRNELYYECCKEPYPDVTYTITMRR 178

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 966965633  69 FYTINLIIPCLLISCLTVLVFYLPSECGEKITLCISVLLSLTVFLLLITEIIPSTSLViPLIGEYLLFTMIFVTLSIVIT 148
Cdd:cd03559    1 YYAVSLLLPSILIMVVSWVGFWLPPDSGERVSFKITLLLTYSVFLIIVSDTLPATPYT-PLIDVYFVVCMALLFIALLET 79

                         90       100
                 ....*....|....*....|....*.
gi 966965633 149 VFVLNVHHRSPRT-HTMPAWVRRVFL 173
Cdd:cd03559   80 IFIVRLVHKQDRVgYVIDRLLRRIFP 105

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  210 PEPEGEPAATSGTQSRHPPS------------PSCVPLDVPAESGPACKSPSDQlPALQPPEAEKASPHPSPGPYRPPHS 277
Cdd:PHA03247 2754 PARPARPPTTAGPPAPAPPAapaagpprrltrPAVASLSESRESLPSPWDPADP-PAAVLAPAAALPPAASPAGPLPPPT 2832

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  278 TQAPGLAKARSLSVQHMSSPGEAVEGGVRCRSRSIQYCVPRDNAA---PEADVQAAGALaSRKTHSAELPPpDQPSPRKC 354
Cdd:PHA03247 2833 SAQPTAPPPPPGPPPPSLPLGGSVAPGGDVRRRPPSRSPAAKPAAparPPVRRLARPAV-SRSTESFALPP-DQPERPPQ 2910

                         170       180
                  ....*....|....*....|....
gi 966965633  355 TCGKEPPSVSPSATLKARSTKAPP 378
Cdd:PHA03247 2911 PQAPPPPQPQPQPPPPPQPQPPPP 2934

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  196 IESMHKMASAPRFWPEPEGEPAATSGTQSRHPPSPSCVPL-------------DVPAES--GPACKSPSDQLPALQPPEA 260
Cdd:PHA03247 2537 IRGLEELASDDAGDPPPPLPPAAPPAAPDRSVPPPRPAPRpsepavtsrarrpDAPPQSarPRAPVDDRGDPRGPAPPSP 2616

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  261 EKASPHP--SPGPYRPPHSTQAPG---LAKARSLSVQHMSSPGEA-VEGGVRCRSRSIQYCVPRDNAAPEADVQAAGALA 334
Cdd:PHA03247 2617 LPPDTHApdPPPPSPSPAANEPDPhppPTVPPPERPRDDPAPGRVsRPRRARRLGRAAQASSPPQRPRRRAARPTVGSLT 2696

                         170       180       190       200       210
                  ....*....|....*....|....*....|....*....|....*....|..
gi 966965633  335 SrkthSAElPPPDQPSPRKCTCGKEPPSVSPSATLKARSTKAPPRHLPLSPA 386
Cdd:PHA03247 2697 S----LAD-PPPPPPTPEPAPHALVSATPLPPGPAAARQASPALPAAPAPPA 2743

transcriptional regulator ICP4; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  200 HKMASAPRFWPEPEGEPAATSGTQSRHPPSPScVPLDVPAESGPACKSPSDQLPALQPPEAEKASPHPSPGPYRPPHSTQ 279
Cdd:PHA03307  142 GSPGPPPAASPPAAGASPAAVASDAASSRQAA-LPLSSPEETARAPSSPPAEPPPSTPPAAASPRPPRRSSPISASASSP 220

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  280 APGLAK-----ARSLSVQHMSSPGEAVEGGVRCR------SRSIQYCVPRDNAAPEADVQAAGALASRKTHSAELPPPDQ 348
Cdd:PHA03307  221 APAPGRsaaddAGASSSDSSSSESSGCGWGPENEcplprpAPITLPTRIWEASGWNGPSSRPGPASSSSSPRERSPSPSP 300

                         170       180       190       200
                  ....*....|....*....|....*....|....*....|....
gi 966965633  349 PSPRKCTCGKEPPSV------SPSATLKARSTKAPPRHLPLSPA 386
Cdd:PHA03307  301 SSPGSGPAPSSPRASssssssRESSSSSTSSSSESSRGAAVSPG 344

Atrophin-1 family; Atrophin-1 is the protein product of the dentatorubral-pallidoluysian atrophy (DRPLA) gene. DRPLA OMIM:125370 is a progressive neurodegenerative disorder. It is caused by the expansion of a CAG repeat in the DRPLA gene on chromosome 12p. This results in an extended polyglutamine region in atrophin-1, that is thought to confer toxicity to the protein, possibly through altering its interactions with other proteins. The expansion of a CAG repeat is also the underlying defect in six other neurodegenerative disorders, including Huntington's disease. One interaction of expanded polyglutamine repeats that is thought to be pathogenic is that with the short glutamine repeat in the transcriptional coactivator CREB binding protein, CBP. This interaction draws CBP away from its usual nuclear location to the expanded polyglutamine repeat protein aggregates that are characteriztic of the polyglutamine neurodegenerative disorders. This interferes with CBP-mediated transcription and causes cytotoxicity.

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  212 PEGEPAATSGTQSRHPP-SPSCVPLDVPAESGPACKSPSDQL-PALQPPEAEKASPHPSPgpyRPPHSTQAPGLAKARSL 289
Cdd:pfam03154 208 PQGSPATSQPPNQTQSTaAPHTLIQQTPTLHPQRLPSPHPPLqPMTQPPPPSQVSPQPLP---QPSLHGQMPPMPHSLQT 284

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  290 SVQHMSSPGEAVEGGVRCRSRSIQYCVPRDNAAPEADVQAAGALASRKTHSAELPPPDQ---PSPRKCTCGKEPPSVSPS 366
Cdd:pfam03154 285 GPSHMQHPVPPQPFPLTPQSSQSQVPPGPSPAAPGQSQQRIHTPPSQSQLQSQQPPREQplpPAPLSMPHIKPPPTTPIP 364

                         170       180       190
                  ....*....|....*....|....*....|..
gi 966965633  367 ATLKARSTKAPPR-----------HLPLSPAL 387
Cdd:pfam03154 365 QLPNPQSHKHPPHlsgpspfqmnsNLPPPPAL 396

transcriptional regulator ICP4; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  216 PAATSGTQSRHPPSPSCVPLDVP---------AESGPACKSPSDQLPALQPPEAEKASPHPSPGPY-RPPHSTQAPGLAK 285
Cdd:PHA03307  200 AAASPRPPRRSSPISASASSPAPapgrsaaddAGASSSDSSSSESSGCGWGPENECPLPRPAPITLpTRIWEASGWNGPS 279

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  286 ARSLSVQHMSSPGEAVEGGVRCRSRSIQYCVPRDNAAPEADVQAAGALASRKTHSAELPPPDQPSPRKCTCGKePPSVSP 365
Cdd:PHA03307  280 SRPGPASSSSSPRERSPSPSPSSPGSGPAPSSPRASSSSSSSRESSSSSTSSSSESSRGAAVSPGPSPSRSPS-PSRPPP 358

                         170       180
                  ....*....|....*....|....*
gi 966965633  366 SATLKARSTKAPPRHLPLSPALTRA 390
Cdd:PHA03307  359 PADPSSPRKRPRPSRAPSSPAASAG 383

DNA polymerase III subunits gamma and tau; Validated

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633 203 ASAPRFWPEPEGEPAAtsgtqsrhPPSPS----CVPLDVPAESGPACKSPSDQLPALQPPEAEKASPHPSPGPYRPPHST 278
Cdd:PRK07764 602 APASSGPPEEAARPAA--------PAAPAapaaPAPAGAAAAPAEASAAPAPGVAAPEHHPKHVAVPDASDGGDGWPAKA 673

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633 279 QAPGLAkARSLSVQHMSSPGEAVEGGVRCRSRSIQYCVPRDNAAPEADVQAAGALASRKTHSAELPPPDQPSPRKCTCGK 358
Cdd:PRK07764 674 GGAAPA-APPPAPAPAAPAAPAGAAPAQPAPAPAATPPAGQADDPAAQPPQAAQGASAPSPAADDPVPLPPEPDDPPDPA 752

                        170       180
                 ....*....|....*....|....*...
gi 966965633 359 EPPSVSPSATLKARSTKAPPRHLPLSPA 386
Cdd:PRK07764 753 GAPAQPPPPPAPAPAAAPAAAPPPSPPS 780

large tegument protein UL36; Provisional

                          10        20        30        40        50        60        70        80
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  203 ASAPRFWPEPEGEPAATSGTQSRHPPSPSCVPldVPAESGpacKSPSDQLPALQPPEAEKASPHPSPGPYRPPHSTQAPG 282
Cdd:PHA03247 2842 PPGPPPPSLPLGGSVAPGGDVRRRPPSRSPAA--KPAAPA---RPPVRRLARPAVSRSTESFALPPDQPERPPQPQAPPP 2916

                          90       100       110       120       130       140       150       160
                  ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633  283 LAKARSLSVQHMSSPGEAVEGgvrcrsrsiqycVPRDNAAPEADVQAAG--ALASRKTHSAELPPPDQPSPRKCTcgkep 360
Cdd:PHA03247 2917 PQPQPQPPPPPQPQPPPPPPP------------RPQPPLAPTTDPAGAGepSGAVPQPWLGALVPGRVAVPRFRV----- 2979

                         170       180
                  ....*....|....*....|....
gi 966965633  361 PSVSPSATLKARSTkAPPRHLPLS 384
Cdd:PHA03247 2980 PQPAPSREAPASST-PPLTGHSLS 3002

DNA polymerase III subunit gamma/tau;

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633 203 ASAPRFWPEPEGEPAATSGTQSRHPPSPSCVPLDVPAESGPACKSPSDQLPALQPPEAEKASPHPSPGPYRPPHSTQAPG 282
Cdd:PRK12323 378 AAAPVAQPAPAAAAPAAAAPAPAAPPAAPAAAPAAAAAARAVAAAPARRSPAPEALAAARQASARGPGGAPAPAPAPAAA 457

                         90       100       110       120       130       140       150       160
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633 283 LAKARSLSVQHMSSPGEAVEGGVRCRSRSIQyCVPRDNAAPEADvQAAGALASrkthsaelPPPDQPSPRKCTCGKEP-P 361
Cdd:PRK12323 458 PAAAARPAAAGPRPVAAAAAAAPARAAPAAA-PAPADDDPPPWE-ELPPEFAS--------PAPAQPDAAPAGWVAESiP 527

                        170       180       190
                 ....*....|....*....|....*....|...
gi 966965633 362 SVSPSATLKARSTKAPPRHLPLSPALTRAVEGV 394
Cdd:PRK12323 528 DPATADPDDAFETLAPAPAAAPAPRAAAATEPV 560

ORF080 virion core protein; Provisional

                         10        20        30        40        50        60        70        80
                 ....*....|....*....|....*....|....*....|....*....|....*....|....*....|....*....|
gi 966965633 238 PAESGPACKSPSDQLPALQPPEAEKASPHPSPGPYRPPHSTQA-PGLAKARSLSVQHMSSPgeaveggvrcrsRSIQYCV 316
Cdd:PHA02682  81 PLAPSPACAAPAPACPACAPAAPAPAVTCPAPAPACPPATAPTcPPPAVCPAPARPAPACP------------PSTRQCP 148

                         90       100       110       120
                 ....*....|....*....|....*....|....*....|....*....
gi 966965633 317 PrdnaAPEADVQAAGALASRKTHSAELPPPDQPSPrKCTCGKEPPSVSP 365
Cdd:PHA02682 149 P----APPLPTPKPAPAAKPIFLHNQLPPPDYPAA-SCPTIETAPAASP 192