RBCC Red Blood Cell Collection

NOS1 [Confidence: low (only semi-automatic identification from reviews)]
Nitric oxide synthase, brain; 1.14.13.39 (Constitutive NOS; NC-NOS; NOS type I; Neuronal NOS; N-NOS; nNOS; Peptidyl-cysteine S-nitrosylase NOS1; bNOS)

UniProt P29475
ID NOS1_HUMAN Reviewed; 1434 AA.
AC P29475; E9PH30; O75713;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-1996, sequence version 2.
DT 22-JAN-2014, entry version 156.
DE RecName: Full=Nitric oxide synthase, brain;
DE EC=1.14.13.39;
DE AltName: Full=Constitutive NOS;
DE AltName: Full=NC-NOS;
DE AltName: Full=NOS type I;
DE AltName: Full=Neuronal NOS;
DE Short=N-NOS;
DE Short=nNOS;
DE AltName: Full=Peptidyl-cysteine S-nitrosylase NOS1;
DE AltName: Full=bNOS;
GN Name=NOS1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
RX PubMed=7528745;
RA Hall A.V., Antoniou H., Wang Y., Cheung A.H., Arbus A.M., Olson S.L.,
RA Lu W.C., Kau C.-L., Marsden P.A.;
RT "Structural organization of the human neuronal nitric oxide synthase
RT gene (NOS1).";
RL J. Biol. Chem. 269:33082-33090(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1 AND 2).
RC TISSUE=Cerebellum;
RX PubMed=7515942;
RA Fujisawa H., Ogura T., Kurashima Y., Yokoyama T., Yamashita J.,
RA Esumi H.;
RT "Expression of two types of nitric oxide synthase mRNA in human
RT neuroblastoma cell lines.";
RL J. Neurochem. 63:140-145(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=7678401; DOI=10.1016/0014-5793(93)81210-Q;
RA Nakane M., Schmidt H.H.H.W., Pollock J.S., Foerstermann U., Murad F.;
RT "Cloned human brain nitric oxide synthase is highly expressed in
RT skeletal muscle.";
RL FEBS Lett. 316:175-180(1993).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Retina;
RX PubMed=8879752; DOI=10.1007/BF02150230;
RA Park C.-S., Gianotti C., Park R., Krishna G.;
RT "Neuronal isoform of nitric oxide synthase is expressed at low levels
RT in human retina.";
RL Cell. Mol. Neurobiol. 16:499-515(1996).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORMS 3 AND 4).
RC TISSUE=Testis;
RX PubMed=9111048; DOI=10.1074/jbc.272.17.11128;
RA Wang Y., Goligorsky M.S., Lin M., Wilcox J.N., Marsden P.A.;
RT "A novel, testis-specific mRNA transcript encoding an NH2-terminal
RT truncated nitric-oxide synthase.";
RL J. Biol. Chem. 272:11392-11401(1997).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS SER-228; ALA-394;
RP ASP-725; ASP-864 AND ARG-1064.
RG NIEHS SNPs program;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 835-901 (ISOFORM 5), AND ALTERNATIVE
RP SPLICING.
RC TISSUE=Skeletal muscle;
RX PubMed=9791007; DOI=10.1006/bbrc.1998.9578;
RA Larsson B., Phillips S.C.;
RT "Isolation and characterization of a novel, human neuronal nitric
RT oxide synthase cDNA.";
RL Biochem. Biophys. Res. Commun. 251:898-902(1998).
CC -!- FUNCTION: Produces nitric oxide (NO) which is a messenger molecule
CC with diverse functions throughout the body. In the brain and
CC peripheral nervous system, NO displays many properties of a
CC neurotransmitter. Probably has nitrosylase activity and mediates
CC cysteine S-nitrosylation of cytoplasmic target proteins such SRR.
CC -!- CATALYTIC ACTIVITY: 2 L-arginine + 3 NADPH + 4 O(2) = 2 L-
CC citrulline + 2 nitric oxide + 3 NADP(+) + 4 H(2)O.
CC -!- COFACTOR: Heme group.
CC -!- COFACTOR: Binds 1 FAD.
CC -!- COFACTOR: Binds 1 FMN.
CC -!- COFACTOR: Tetrahydrobiopterin (BH4). May stabilize the dimeric
CC form of the enzyme.
CC -!- ENZYME REGULATION: Stimulated by calcium/calmodulin. Inhibited by
CC n-Nos-inhibiting protein (PIN) which may prevent the dimerization
CC of the protein. Inhibited by NOSIP.
CC -!- SUBUNIT: Homodimer. Interacts with DLG4; the interaction possibly
CC being prevented by the association between NOS1 and CAPON. Forms a
CC ternary complex with CAPON and RASD1. Forms a ternary complex with
CC CAPON and SYN1. Interacts with ZDHHC23. Interacts with NOSIP;
CC which may impair its synaptic location (By similarity). Interacts
CC with HTR4. Interacts with VAC14 (By similarity). Interacts with
CC SLC6A4 (By similarity). Interacts (via N-terminus domain) with
CC DLG4 (via N-terminus tandem pair of PDZ domains) (By similarity).
CC -!- INTERACTION:
CC Q08AM6:VAC14; NbExp=5; IntAct=EBI-7164065, EBI-2107455;
CC -!- SUBCELLULAR LOCATION: Cell membrane, sarcolemma; Peripheral
CC membrane protein. Cell projection, dendritic spine (By
CC similarity). Note=In skeletal muscle, it is localized beneath the
CC sarcolemma of fast-twitch muscle fiber by associating with the
CC dystrophin glycoprotein complex. In neurons, enriched in dendritic
CC spines (By similarity).
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Comment=Isoform 3 is produced by different alternative splicing
CC events implicating either the untranslated exons TEX1 (TN-NOS)
CC or TEX1B (TN-NOSB) leading to a N-terminus truncated protein
CC which possesses enzymatic activity comparable to that of isoform
CC 1. The C-terminal truncated isoform 4 is produced by insertion
CC of the TEX2 exon between exons 3 and 4 of isoform 1, leading to
CC a frameshift and a premature stop codon;
CC Name=1; Synonyms=N-NOS-1;
CC IsoId=P29475-1; Sequence=Displayed;
CC Name=2; Synonyms=N-NOS-2;
CC IsoId=P29475-2; Sequence=VSP_003574;
CC Name=3; Synonyms=TN-NOS, TN-NOSB;
CC IsoId=P29475-3; Sequence=VSP_003571;
CC Name=4; Synonyms=TEX2-insertion;
CC IsoId=P29475-4; Sequence=VSP_003572, VSP_003573;
CC Name=5; Synonyms=nNOSmu;
CC IsoId=P29475-5; Sequence=VSP_044916;
CC -!- TISSUE SPECIFICITY: Isoform 1 is ubiquitously expressed: detected
CC in skeletal muscle and brain, also in testis, lung and kidney, and
CC at low levels in heart, adrenal gland and retina. Not detected in
CC the platelets. Isoform 3 is expressed only in testis. Isoform 4 is
CC detected in testis, skeletal muscle, lung, and kidney, at low
CC levels in the brain, but not in the heart and adrenal gland.
CC -!- DOMAIN: The PDZ domain in the N-terminal part of the neuronal
CC isoform participates in protein-protein interaction, and is
CC responsible for targeting nNos to synaptic membranes in muscles.
CC Mediates interaction with VAC14 (By similarity).
CC -!- PTM: Ubiquitinated; mediated by STUB1/CHIP in the presence of
CC Hsp70 and Hsp40 (in vitro) (By similarity).
CC -!- SIMILARITY: Belongs to the NOS family.
CC -!- SIMILARITY: Contains 1 FAD-binding FR-type domain.
CC -!- SIMILARITY: Contains 1 flavodoxin-like domain.
CC -!- SIMILARITY: Contains 1 PDZ (DHR) domain.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/nos1/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Nitric oxide synthase entry;
CC URL="http://en.wikipedia.org/wiki/Nitric_oxide_synthase";
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DR EMBL; U17327; AAA62405.1; -; mRNA.
DR EMBL; U17326; AAB60654.1; ALT_SEQ; Genomic_DNA.
DR EMBL; U17299; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17300; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17301; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17302; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17303; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17304; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17305; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17307; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17308; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17309; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17310; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17311; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17312; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17313; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17314; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17315; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17316; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17317; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17318; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17319; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17320; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17321; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17322; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17323; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17324; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; U17325; AAB60654.1; JOINED; Genomic_DNA.
DR EMBL; D16408; BAA03895.1; -; mRNA.
DR EMBL; L02881; AAA36376.1; -; mRNA.
DR EMBL; U31466; AAB49040.1; -; mRNA.
DR EMBL; U66362; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AY445095; AAR07069.1; -; Genomic_DNA.
DR EMBL; AC026364; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC068799; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AC073864; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AJ004918; CAA06218.1; -; mRNA.
DR PIR; G01946; G01946.
DR RefSeq; NP_000611.1; NM_000620.4.
DR RefSeq; NP_001191142.1; NM_001204213.1.
DR RefSeq; NP_001191143.1; NM_001204214.1.
DR RefSeq; NP_001191147.1; NM_001204218.1.
DR UniGene; Hs.654410; -.
DR UniGene; Hs.684465; -.
DR UniGene; Hs.684466; -.
DR UniGene; Hs.684467; -.
DR UniGene; Hs.735734; -.
DR ProteinModelPortal; P29475; -.
DR SMR; P29475; 12-126, 303-721, 755-1418.
DR IntAct; P29475; 3.
DR MINT; MINT-122019; -.
DR STRING; 9606.ENSP00000320758; -.
DR BindingDB; P29475; -.
DR ChEMBL; CHEMBL2096621; -.
DR DrugBank; DB00155; L-Citrulline.
DR GuidetoPHARMACOLOGY; 1251; -.
DR PhosphoSite; P29475; -.
DR DMDM; 1709333; -.
DR PaxDb; P29475; -.
DR PRIDE; P29475; -.
DR DNASU; 4842; -.
DR Ensembl; ENST00000317775; ENSP00000320758; ENSG00000089250.
DR Ensembl; ENST00000338101; ENSP00000337459; ENSG00000089250.
DR GeneID; 4842; -.
DR KEGG; hsa:4842; -.
DR UCSC; uc001twm.2; human.
DR CTD; 4842; -.
DR GeneCards; GC12M117636; -.
DR HGNC; HGNC:7872; NOS1.
DR HPA; CAB002167; -.
DR MIM; 163731; gene.
DR neXtProt; NX_P29475; -.
DR PharmGKB; PA252; -.
DR eggNOG; COG4362; -.
DR HOGENOM; HOG000220884; -.
DR HOVERGEN; HBG000159; -.
DR KO; K13240; -.
DR OMA; NQMVKVE; -.
DR OrthoDB; EOG79SDW7; -.
DR BioCyc; MetaCyc:HS01647-MONOMER; -.
DR Reactome; REACT_116125; Disease.
DR Reactome; REACT_604; Hemostasis.
DR ChiTaRS; NOS1; human.
DR GeneWiki; NOS1; -.
DR GenomeRNAi; 4842; -.
DR NextBio; 18658; -.
DR PMAP-CutDB; P29475; -.
DR PRO; PR:P29475; -.
DR ArrayExpress; P29475; -.
DR Bgee; P29475; -.
DR CleanEx; HS_NOS1; -.
DR Genevestigator; P29475; -.
DR GO; GO:0005856; C:cytoskeleton; ISS:BHF-UCL.
DR GO; GO:0005829; C:cytosol; TAS:Reactome.
DR GO; GO:0043197; C:dendritic spine; IEA:UniProtKB-SubCell.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; ISS:BHF-UCL.
DR GO; GO:0001917; C:photoreceptor inner segment; ISS:BHF-UCL.
DR GO; GO:0043234; C:protein complex; ISS:BHF-UCL.
DR GO; GO:0042383; C:sarcolemma; IDA:BHF-UCL.
DR GO; GO:0016529; C:sarcoplasmic reticulum; IDA:BHF-UCL.
DR GO; GO:0045202; C:synapse; IEA:Ensembl.
DR GO; GO:0034618; F:arginine binding; TAS:BHF-UCL.
DR GO; GO:0046870; F:cadmium ion binding; ISS:BHF-UCL.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; ISS:BHF-UCL.
DR GO; GO:0010181; F:FMN binding; ISS:BHF-UCL.
DR GO; GO:0020037; F:heme binding; ISS:BHF-UCL.
DR GO; GO:0044325; F:ion channel binding; ISS:BHF-UCL.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0050661; F:NADP binding; ISS:BHF-UCL.
DR GO; GO:0003958; F:NADPH-hemoprotein reductase activity; IBA:RefGenome.
DR GO; GO:0004517; F:nitric-oxide synthase activity; ISS:BHF-UCL.
DR GO; GO:0097110; F:scaffold protein binding; ISS:BHF-UCL.
DR GO; GO:0017080; F:sodium channel regulator activity; ISS:BHF-UCL.
DR GO; GO:0034617; F:tetrahydrobiopterin binding; NAS:BHF-UCL.
DR GO; GO:0006527; P:arginine catabolic process; IC:BHF-UCL.
DR GO; GO:0007596; P:blood coagulation; TAS:Reactome.
DR GO; GO:0071363; P:cellular response to growth factor stimulus; IEA:Ensembl.
DR GO; GO:0042738; P:exogenous drug catabolic process; IEA:Ensembl.
DR GO; GO:0051701; P:interaction with host; TAS:Reactome.
DR GO; GO:0033555; P:multicellular organismal response to stress; IMP:BHF-UCL.
DR GO; GO:0007520; P:myoblast fusion; TAS:BHF-UCL.
DR GO; GO:0045776; P:negative regulation of blood pressure; IBA:RefGenome.
DR GO; GO:0010523; P:negative regulation of calcium ion transport into cytosol; TAS:BHF-UCL.
DR GO; GO:0051346; P:negative regulation of hydrolase activity; IEA:Ensembl.
DR GO; GO:0043267; P:negative regulation of potassium ion transport; IEA:Ensembl.
DR GO; GO:0051612; P:negative regulation of serotonin uptake; IEA:Ensembl.
DR GO; GO:0042136; P:neurotransmitter biosynthetic process; TAS:BHF-UCL.
DR GO; GO:0006809; P:nitric oxide biosynthetic process; ISS:BHF-UCL.
DR GO; GO:0007263; P:nitric oxide mediated signal transduction; IBA:RefGenome.
DR GO; GO:0018119; P:peptidyl-cysteine S-nitrosylation; ISS:BHF-UCL.
DR GO; GO:0090382; P:phagosome maturation; TAS:Reactome.
DR GO; GO:0031284; P:positive regulation of guanylate cyclase activity; IBA:RefGenome.
DR GO; GO:0035066; P:positive regulation of histone acetylation; IEA:Ensembl.
DR GO; GO:1902307; P:positive regulation of sodium ion transmembrane transport; ISS:BHF-UCL.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; IEA:Ensembl.
DR GO; GO:0045909; P:positive regulation of vasodilation; IDA:BHF-UCL.
DR GO; GO:0055117; P:regulation of cardiac muscle contraction; TAS:BHF-UCL.
DR GO; GO:0009408; P:response to heat; IDA:BHF-UCL.
DR GO; GO:0001666; P:response to hypoxia; IEP:BHF-UCL.
DR GO; GO:0006941; P:striated muscle contraction; IEA:Ensembl.
DR Gene3D; 1.20.990.10; -; 1.
DR Gene3D; 3.90.340.10; -; 1.
DR InterPro; IPR003097; FAD-binding_1.
DR InterPro; IPR017927; Fd_Rdtase_FAD-bd.
DR InterPro; IPR001094; Flavdoxin.
DR InterPro; IPR008254; Flavodoxin/NO_synth.
DR InterPro; IPR001709; Flavoprot_Pyr_Nucl_cyt_Rdtase.
DR InterPro; IPR023173; NADPH_Cyt_P450_Rdtase_dom3.
DR InterPro; IPR004030; NO_synthase_oxygenase_dom.
DR InterPro; IPR012144; NOS_euk.
DR InterPro; IPR001433; OxRdtase_FAD/NAD-bd.
DR InterPro; IPR001478; PDZ.
DR InterPro; IPR017938; Riboflavin_synthase-like_b-brl.
DR Pfam; PF00667; FAD_binding_1; 1.
DR Pfam; PF00258; Flavodoxin_1; 1.
DR Pfam; PF00175; NAD_binding_1; 1.
DR Pfam; PF02898; NO_synthase; 1.
DR Pfam; PF00595; PDZ; 1.
DR PIRSF; PIRSF000333; NOS; 1.
DR PRINTS; PR00369; FLAVODOXIN.
DR PRINTS; PR00371; FPNCR.
DR SMART; SM00228; PDZ; 1.
DR SUPFAM; SSF50156; SSF50156; 1.
DR SUPFAM; SSF56512; SSF56512; 1.
DR SUPFAM; SSF63380; SSF63380; 1.
DR PROSITE; PS51384; FAD_FR; 1.
DR PROSITE; PS50902; FLAVODOXIN_LIKE; 1.
DR PROSITE; PS60001; NOS; 1.
DR PROSITE; PS50106; PDZ; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Calmodulin-binding; Cell membrane;
KW Cell projection; Complete proteome; FAD; Flavoprotein; FMN; Heme;
KW Iron; Membrane; Metal-binding; NADP; Oxidoreductase; Polymorphism;
KW Reference proteome; Ubl conjugation.
FT CHAIN 1 1434 Nitric oxide synthase, brain.
FT /FTId=PRO_0000170921.
FT DOMAIN 17 99 PDZ.
FT DOMAIN 760 940 Flavodoxin-like.
FT DOMAIN 995 1242 FAD-binding FR-type.
FT NP_BIND 886 917 FMN (By similarity).
FT NP_BIND 1032 1043 FAD (By similarity).
FT NP_BIND 1175 1185 FAD (By similarity).
FT NP_BIND 1250 1268 NADP (By similarity).
FT NP_BIND 1348 1363 NADP (By similarity).
FT REGION 1 205 Interaction with NOSIP (By similarity).
FT REGION 163 245 PIN (nNOS-inhibiting protein) binding.
FT REGION 730 750 Calmodulin-binding (Potential).
FT REGION 755 774 Tetrahydrobiopterin-binding (By
FT similarity).
FT METAL 420 420 Iron (heme axial ligand) (By similarity).
FT VAR_SEQ 1 336 Missing (in isoform 3).
FT /FTId=VSP_003571.
FT VAR_SEQ 285 407 PPTSGKQSPTKNGSPSKCPRFLKVKNWETEVVLTDTLHLKS
FT TLETGCTEYICMGSIMHPSQHARRPEDVRTKGQLFPLAKEF
FT IDQYYSSIKRFGSKAHMERLEEVNKEIDTTSTYQLKDTELI
FT -> MRKLRITEGFGVQRGSHNHPPPQENSPPQRMAAPPSVH
FT ASSRSRTGRLRWFSLTPSTLRAHWKRDALSTSAWAPSCILL
FT SMQGGLKTSAQKDSSSLSPKSLLINTIHQLKDLAPKPTWKG
FT WKR (in isoform 4).
FT /FTId=VSP_003572.
FT VAR_SEQ 408 1434 Missing (in isoform 4).
FT /FTId=VSP_003573.
FT VAR_SEQ 509 613 Missing (in isoform 2).
FT /FTId=VSP_003574.
FT VAR_SEQ 844 844 K -> KYPEPLRFFPRKGPPLPNGDTEVHGLAAARDSQHR
FT (in isoform 5).
FT /FTId=VSP_044916.
FT VARIANT 228 228 P -> S (in dbSNP:rs9658279).
FT /FTId=VAR_018948.
FT VARIANT 394 394 D -> A (in dbSNP:rs9658356).
FT /FTId=VAR_018949.
FT VARIANT 725 725 N -> D (in dbSNP:rs9658403).
FT /FTId=VAR_018950.
FT VARIANT 864 864 G -> D (in dbSNP:rs9658445).
FT /FTId=VAR_018951.
FT VARIANT 1064 1064 Q -> R (in dbSNP:rs9658482).
FT /FTId=VAR_018952.
FT CONFLICT 131 131 K -> E (in Ref. 4; AAB49040).
FT CONFLICT 178 184 LAPRPPG -> WPQAPR (in Ref. 3 and 4).
FT CONFLICT 492 493 QP -> HR (in Ref. 3; AAA36376).
FT CONFLICT 549 549 V -> L (in Ref. 3; AAA36376).
FT CONFLICT 563 563 G -> A (in Ref. 3; AAA36376).
FT CONFLICT 1407 1407 Y -> I (in Ref. 3; AAA36376).
SQ SEQUENCE 1434 AA; 160970 MW; 99235793B953BF37 CRC64;
MEDHMFGVQQ IQPNVISVRL FKRKVGGLGF LVKERVSKPP VIISDLIRGG AAEQSGLIQA
GDIILAVNGR PLVDLSYDSA LEVLRGIASE THVVLILRGP EGFTTHLETT FTGDGTPKTI
RVTQPLGPPT KAVDLSHQPP AGKEQPLAVD GASGPGNGPQ HAYDDGQEAG SLPHANGLAP
RPPGQDPAKK ATRVSLQGRG ENNELLKEIE PVLSLLTSGS RGVKGGAPAK AEMKDMGIQV
DRDLDGKSHK PLPLGVENDR VFNDLWGKGN VPVVLNNPYS EKEQPPTSGK QSPTKNGSPS
KCPRFLKVKN WETEVVLTDT LHLKSTLETG CTEYICMGSI MHPSQHARRP EDVRTKGQLF
PLAKEFIDQY YSSIKRFGSK AHMERLEEVN KEIDTTSTYQ LKDTELIYGA KHAWRNASRC
VGRIQWSKLQ VFDARDCTTA HGMFNYICNH VKYATNKGNL RSAITIFPQR TDGKHDFRVW
NSQLIRYAGY KQPDGSTLGD PANVQFTEIC IQQGWKPPRG RFDVLPLLLQ ANGNDPELFQ
IPPELVLEVP IRHPKFEWFK DLGLKWYGLP AVSNMLLEIG GLEFSACPFS GWYMGTEIGV
RDYCDNSRYN ILEEVAKKMN LDMRKTSSLW KDQALVEINI AVLYSFQSDK VTIVDHHSAT
ESFIKHMENE YRCRGGCPAD WVWIVPPMSG SITPVFHQEM LNYRLTPSFE YQPDPWNTHV
WKGTNGTPTK RRAIGFKKLA EAVKFSAKLM GQAMAKRVKA TILYATETGK SQAYAKTLCE
IFKHAFDAKV MSMEEYDIVH LEHETLVLVV TSTFGNGDPP ENGEKFGCAL MEMRHPNSVQ
EERKSYKVRF NSVSSYSDSQ KSSGDGPDLR DNFESAGPLA NVRFSVFGLG SRAYPHFCAF
GHAVDTLLEE LGGERILKMR EGDELCGQEE AFRTWAKKVF KAACDVFCVG DDVNIEKANN
SLISNDRSWK RNKFRLTFVA EAPELTQGLS NVHKKRVSAA RLLSRQNLQS PKSSRSTIFV
RLHTNGSQEL QYQPGDHLGV FPGNHEDLVN ALIERLEDAP PVNQMVKVEL LEERNTALGV
ISNWTDELRL PPCTIFQAFK YYLDITTPPT PLQLQQFASL ATSEKEKQRL LVLSKGLQEY
EEWKWGKNPT IVEVLEEFPS IQMPATLLLT QLSLLQPRYY SISSSPDMYP DEVHLTVAIV
SYRTRDGEGP IHHGVCSSWL NRIQADELVP CFVRGAPSFH LPRNPQVPCI LVGPGTGIAP
FRSFWQQRQF DIQHKGMNPC PMVLVFGCRQ SKIDHIYREE TLQAKNKGVF RELYTAYSRE
PDKPKKYVQD ILQEQLAESV YRALKEQGGH IYVCGDVTMA ADVLKAIQRI MTQQGKLSAE
DAGVFISRMR DDNRYHEDIF GVTLRTYEVT NRLRSESIAF IEESKKDTDE VFSS
//

MIM 163731
*RECORD*
*FIELD* NO
163731
*FIELD* TI
*163731 NITRIC OXIDE SYNTHASE 1; NOS1
NITRIC OXIDE SYNTHASE, NEURONAL, INCLUDED;;
NITRIC OXIDE SYNTHASE, PENILE NEURONAL, INCLUDED; PNNOS, INCLUDED
read more*FIELD* TX

DESCRIPTION

Nitric oxide (NO) is a messenger molecule with diverse functions
throughout the body. In the brain and peripheral nervous system, NO
displays many properties of a neurotransmitter; it is implicated in
neurotoxicity associated with stroke and neurodegenerative diseases,
neural regulation of smooth muscle, including peristalsis, and penile
erection. NO is also responsible for endothelium-derived relaxing factor
activity regulating blood pressure. In macrophages, NO mediates
tumoricidal and bactericidal actions, as indicated by the fact that
inhibitors of NO synthase (NOS) block these effects. Neuronal NOS and
macrophage NOS (163730) are distinct isoforms (Lowenstein et al., 1992).
Both the neuronal and the macrophage forms are unusual among oxidative
enzymes in requiring several electron donors: FAD (see 610595), flavin
mononucleotide (FMN), NADPH, and tetrahydrobiopterin.

CLONING

Bredt et al. (1991) cloned a cDNA for the neuronal form of nitric oxide
(NO) synthase and studied its expression. The only mammalian protein
with close sequence similarity was cytochrome P450 reductase.

Magee et al. (1996) used PCR to clone a novel form of neuronal NOS from
rat penile RNA. This NOS cDNA was termed PnNOS for 'penile neuronal
NOS.' Sequencing revealed that the PnNOS cDNA was identical to rat
cerebellar neuronal NOS1 except for a 102-bp insertion in PnNOS,
indicating that PnNOS is a novel isoform. PCR of a human penile cDNA
library confirmed that this insert is present in human DNA at the same
location. Repetition of RT-PCR showed PnNOS to be the only form of NOS1
expressed in rat penis, urethra, prostate, and skeletal muscle. The
PnNOS form was also present in rat cerebellum, liver, and pelvic plexus,
although less abundantly than the shorter isoform. The authors
postulated that PnNOS may be responsible for the synthesis of nitric
oxide during penile erection and may be involved in control of the tone
of the urethra, prostate, and bladder.

Wang et al. (1997) identified an nNOS splice variant, expressed in
testis, that encodes an N-terminally truncated protein of 1,098 amino
acids. Upon expression in CHO-K1 cells, this variant displayed
calcium-dependent nitric oxide synthase activity with catalytic activity
comparable to that of full-length nNOS.

Newton et al. (2003) identified a variant with an 89-bp insertion within
the 5-prime untranslated region. The reading frame was unaffected. This
mRNA accounted for 5 to 40% of nNOS transcripts in several tissues and
was enriched in testis, brain, skeletal muscle, and lung.

GENE STRUCTURE

NOS1 cDNA clones contain different 5-prime terminal exons spliced to a
common exon 2. By genomic cloning and sequence analysis, Xie et al.
(1995) demonstrated that the unique exons are positioned within 300 bp
of each other but separated from exon 2 by an intron that is at least 20
kb long. A CpG island engulfs the downstream 5-prime terminal exon. In
contrast, most of the upstream exon resides outside of this CpG island.
Furthermore, the upstream exon includes a GT dinucleotide repeat. By
expressing fusion genes in transfected HeLa cells, Xie et al. (1995)
showed that expression of these 2 exons is subject to transcriptional
control by separate promoters. However, the proximity of these promoters
raises the possibility that complex interactions may be involved in
regulating NOS1 gene expression at these sites.

Wang et al. (1997) determined that the promoter region of a splice
variant they isolated from testis does not contain canonical TATA and
CAAT boxes. It does contain multiple putative cis regulatory elements,
including those implicated in testis-specific gene expression.

A common variant described by Newton et al. (2003), which contains an
89-bp insertion in the promoter region, was predicted to form a
stem-loop secondary structure.

MAPPING

Using a rat cDNA probe prepared from rat cerebellum RNA, Kishimoto et
al. (1992) isolated a human nitric oxide synthase cDNA from a human
cerebellum cDNA library. This in turn was used for Southern blot
analysis of DNAs from human-rodent hybrid cell lines to map the NOS1
gene to 12q14-qter. Marsden et al. (1993) regionalized the NOS1 gene to
12q24.2 by fluorescence in situ hybridization. Xu et al. (1993) used
fluorescence in situ hybridization to map the NOS1 gene to
12q24.2-q24.31. Lee et al. (1995) assigned the homologous gene to mouse
chromosome 5 by analysis of interspecific backcrosses.

GENE FUNCTION

Burnett et al. (1992) localized NO synthase to rat penile neurons
innervating the corpora cavernosa and to neuronal plexuses in the
adventitial layer of penile arteries. They found, furthermore, that
small doses of NO synthase inhibitors abolished electrophysiologically
induced penile erections. Thus, they established that nitric oxide is a
physiologic mediator of erectile function.

Kharazia et al. (1994) found that all neurons in the striatum were
positive for nitric oxide. Synthase staining showed that they were also
positive for diaphorase. The 2 activities colocalized in the majority of
cortical neurons, but 1% of neurons intensely stained for diaphorase
lacked detectable levels of nitric oxide synthase. Kharazia et al.
(1994) suggested that these single-labeled neurons (0.01% of cortical
neurons) might contain either a splice variant or a novel isoform of
NOS.

Deans et al. (1996) found that the OCT2 (164176) transcription factor
binds to the downstream 5.1 promoter but not the upstream 5.2 promoter
of the neuronal NOS promoter region. OCT2 may activate transcription of
neuronal NOS specifically in neuronal cells.

Nitric oxide is synthesized in skeletal muscle by neuronal-type NO
synthase, which is localized to sarcolemma of fast-twitch fibers.
Synthesis of NO in active muscle opposes contractile force. Brenman et
al. (1995) showed that NOS1 partitions with skeletal muscle membranes
owing to association of enzyme with dystrophin (300377), the protein
mutated in Duchenne muscular dystrophy (DMD; 310200). The dystrophin
complex interacts with an N-terminal domain of NOS1 that contains a GLGF
motif. Both humans with DMD and mdx mice show a selective loss of NOS1
protein and catalytic activity from muscle membranes, demonstrating a
novel role for dystrophin and localizing a signaling enzyme to the
myocyte sarcolemma. Brenman et al. (1995) speculated that aberrant
regulation of NOS1 may contribute to preferential degeneration of
fast-twitch muscle fibers in DMD.

The neuronal isoform of nitric oxide synthase is highly expressed in
mammalian skeletal muscle. Since NO had been implicated in the local
metabolic regulation of blood flow in contracting skeletal muscle in
part by antagonizing sympathetic vasoconstriction, Thomas et al. (1998)
hypothesized that NOS1 in skeletal muscle is the source of the NO
mediating the inhibition of sympathetic vasoconstriction in contracting
muscle. In the mdx mouse, a model of DMD in which dystrophin deficiency
results in greatly reduced expression of NOS1 in skeletal muscle, Thomas
et al. (1998) found that the normal ability of skeletal muscle
contraction to attenuate alpha-adrenergic vasoconstriction is defective.
Similar results were obtained in mutant mice that lack the gene encoding
NOS1. Together these data suggested a specific role for NOS1 in the
local metabolic inhibition of alpha-adrenergic vasoconstriction in
active skeletal muscle.

The relevance of the observations in mice to Duchenne muscular dystrophy
in children was demonstrated by Sander et al. (2000). They reported that
the protective mechanism that NOS1 provides to exercising skeletal
muscle by blunting the vasoconstrictor response to alpha-adrenergic
receptor activation is defective in children with DMD. Vasoconstrictor
response (measured as a decrease in muscle oxygenation) to reflex
sympathetic activation was not blunted during exercise of the dystrophic
muscles. In contrast, this protective mechanism was intact in healthy
children and in those with polymyositis or limb-girdle muscular
dystrophy, both muscle diseases that do not result in loss of neuronal
nitric oxide synthase. In both mouse and human skeletal muscle,
dystrophin deficiency results in loss of neuronal nitric oxide synthase,
which normally is localized to the sarcolemma as part of the
dystrophin-glycoprotein complex. The clinical observations of Sander et
al. (2000) suggested that unopposed sympathetic vasoconstriction in
exercising human skeletal muscle may constitute a vascular mechanism
contributing to the pathogenesis of DMD.

Paraquat is a pneumotoxicant that produces toxicity by redox cycling
with cellular diaphorases, thereby elevating intracellular levels of
superoxide. NO synthase participates in paraquat-induced lung injury. It
had been theorized that NO reacts with superoxide generated by paraquat
to produce the toxin peroxynitrite. Day et al. (1999) asked whether NOS
might alternatively function as a paraquat diaphorase and reexamined the
question of whether NO/superoxide reactions are toxic or protective.
They showed that neuronal NOS had paraquat diaphorase activity that
inversely correlates with NO formation; that paraquat-induced
endothelial cell toxicity is attenuated by inhibitors of NOS that
prevent NADPH oxidation, but is not attenuated by those that do not;
that paraquat inhibits endothelium-derived, but not NO-induced,
relaxations of aortic rings; and that paraquat-induced cytotoxicity is
potentiated in cytokine-activated macrophages in a manner that
correlates with its ability to block NO formation. These data indicated
that NOS is a paraquat diaphorase and that toxicity of such redox-active
compounds involves the loss of NO-related activity.

Using sea urchin gametes, Kuo et al. (2000) showed that nitric oxide
synthase is present at high concentration and active in sperm after
activation by the acrosome reaction. An increase in nitrostatin within
eggs is evident seconds after insemination and precedes the calcium
pulse of fertilization. Microinjection of nitric oxide donors or
recombinant nitric oxide synthase recapitulates events of egg
activation, whereas prior injection of oxyhemoglobin, a physiologic
nitric oxide scavenger, prevented egg activation after fertilization.
Kuo et al. (2000) concluded that nitric oxide synthase and nitric
oxide-related bioactivity satisfied the primary criteria of an egg
activator: they are present in an appropriate place, active at an
appropriate time, and are necessary and sufficient for successful
fertilization. They suggested that nitric oxide may be a universal
activator of eggs or oocytes.

Gu et al. (2002) reported activation of matrix metalloproteinase-9
(MMP9; 120361) by Nos1 in a mouse model of cerebral ischemia.
Immunochemical analysis of the ischemic cortex following stroke in
wildtype animals showed that activated Mmp9 colocalized with Nos1 within
neurons. Activation of Mmp9 was abrogated after stroke in Nos1-null mice
or in wildtype mice treated with an NOS inhibitor. Biochemical analysis
and mass spectrometry revealed that MMP9 activation is initiated by NOS1
through S-nitrosylation of the Zn(2+)-coordinating cysteine within the
active site of MMP9. Further oxidation causes irreversible modification
of the residue to sulfinic or sulfonic acid. Gu et al. (2002) noted that
the regulation of protein function by S-nitrosylation may function as a
posttranslational modification analogous to phosphorylation or
acetylation.

Raoul et al. (2002) showed that Fas (134637), a member of the death
receptor family, triggers cell death specifically in motor neurons by
transcriptional upregulation of nNOS mediated by p38 kinase (600289).
ASK1 (602448) and Daxx (603186) act upstream of p38 in the Fas signaling
pathway. The authors also showed that synergistic activation of the NO
pathway and the classic FADD (602457)/caspase-8 (601763) cell death
pathway were needed for motor neuron cell death. No evidence for
involvement of the Fas/NO pathway was found in other cell types. Motor
neurons from transgenic mice expressing amyotrophic lateral sclerosis
(ALS; 105400)-linked SOD1 (147450) mutations displayed increased
susceptibility to activation of the Fas/NO pathway. Raoul et al. (2002)
emphasized that this signaling pathway was unique to motor neurons and
suggested that these cell pathways may contribute to motor neuron loss
in ALS.

Using a homogenized mouse heart preparation, Khan et al. (2004)
demonstrated that xanthine oxidoreductase (XDH; 607633) and Nos1
coimmunoprecipitate and colocalize in the cardiac sarcoplasmic
reticulum. Deficiency of Nos1 (but not Nos3; 163729) led to marked
increases in Xdh-mediated superoxide production, which in turn depressed
myocardial excitation-contraction coupling in a manner reversible by Xdh
inhibition. Khan et al. (2004) concluded that NOS1 has a direct
antioxidant mechanism via its interaction with XDH.

Following exposure of rats to hypoxic conditions (8% oxygen), Ward et
al. (2005) found Nos1 protein increased in aorta, mesenteric arterioles,
pulmonary arteries, brain, and diaphragm. NOS1 expression increased in
human aortic smooth muscle cells after hypoxic incubation (1% oxygen).
Ca(2+)-dependent NOS activity was increased in endothelium-denuded
aortic segments from hypoxia-exposed rats. NOS1 inhibition enhanced the
contractile responses of endothelium-denuded aortic rings and mesenteric
arterioles from hypoxia-exposed rats but not from normoxic rats. The
hypoxia-inducible mRNA expressed by human cells contained a novel
5-prime UTR, and transgenic mice possessing a reporter gene under the
control of the 5-prime UTR and the immediate 5-prime flanking region
demonstrated expression of the reporter after exposure to hypoxia in the
aorta, mesenteric arterioles, renal papilla, and brain. Ward et al.
(2005) concluded that this hypoxia-responsive NOS1 promoter gives rise
to rapid translation and is distinct from NOS1 promoters involved in
constitutive and cell-restricted NOS1 expression.

Using mouse models, Kobayashi et al. (2008) demonstrated that the
exaggerated exercise-induced fatigue response seen in many neuromuscular
disorders is distinct from a loss in specific force production by
muscle, and that sarcolemma-localized signaling by nNOS in skeletal
muscle is required to maintain activity after mild exercise. Kobayashi
et al. (2008) showed that nNOS-null mice do not have muscle pathology
and have no loss of muscle-specific force after exercise but do display
this exaggerated fatigue response to mild exercise. In mouse models of
nNOS mislocalization from the sarcolemma, prolonged inactivity was
relieved only by pharmacologically enhancing the cGMP signal that
results from muscle nNOS activation during the nitric oxide signaling
response to mild exercise. These findings suggested that the mechanism
underlying the exaggerated fatigue response to mild exercise is a lack
of contraction-induced signaling from sarcolemma-localized nNOS, which
decreases cGMP-mediated vasomodulation in the vessels that supply active
muscle after mild exercise. Sarcolemmal nNOS staining was decreased in
patient biopsies from a large number of distinct myopathies, suggesting
a common mechanism of fatigue. Kobayashi et al. (2008) concluded that
patients with an exaggerated fatigue response to mild exercise would
show clinical improvement in response to treatment strategies aimed at
improving exercise-induced signaling.

Neuronal NOS localizes to the sarcolemma via direct binding to
alpha-1-syntrophin (SNTA1; 601017) and interaction with dystrophin. In a
retrospective study of 161 patients with acquired and nondystrophin
inherited neuromuscular disorders, Finanger-Hedderick et al. (2011)
found that 70 (43%) had abnormal sarcolemmal staining of nNOS. These
included 42% of those with inherited myopathic conditions, including 59%
of those with unspecified congenital myopathy; 25% of those with
acquired myopathic conditions, mostly inflammatory myopathy; 57% of
those with denervating conditions, mainly spinal muscular atrophy (SMA;
253300); and 93% with hypotonia, most of whom likely had an unidentified
single gene disorder. The findings indicated that nNOS mislocalization
can be observed in a broad range of neuromuscular conditions independent
of the primary cause. There was a significant correlation between
abnormal sarcolemmal nNOS staining and compromised mobility status
and/or compromised muscle function. Two mouse models of muscle atrophy,
those administered high-dose steroids and who underwent short-term
starvation, both showed absent or severely reduced sarcolemmal staining
of nNOS even without decreased protein levels and in the presence of
preserved mobility, suggesting that catabolic stress may be associated
with sarcolemmal loss of nNOS. However, muscle tissue from hibernating
squirrels, who had no muscle atrophy, showed preservation of sarcolemmal
nNOS, indicating complex regulation. The report indicated that nNOS
mislocalization plays a role in secondary pathophysiologic processes and
suggested that preservation of nNOS may be significant in maintaining
muscle homeostasis.

MOLECULAR GENETICS

Parkinson disease (PD; 168600) is a neurodegenerative disorder which
leads to selective loss of nigral dopaminergic neurons. Inhibition of
neuronal NOS (nNOS) and inducible NOS (iNOS) has been shown to result in
neuroprotective effects in the model of PD caused by exposure to MPTP, a
dopaminergic neurotoxin that is an analog of the pesticide paraquat.
Levecque et al. (2003) performed a community-based case-control study of
209 PD patients enrolled in a French health insurance organization for
agricultural workers and 488 European controls. Associations were
observed with a G-to-A polymorphism in exon 22 of iNOS, designated iNOS
22 (OR for AA carriers, 0.50; 95% CI, 0.29-0.86; p = 0.01) and a T-to-C
polymorphism in exon 29 of nNOS, designated nNOS 29 (OR for carriers of
the T allele, 1.53; 95% CI, 1.08-2.16; p = 0.02). No association was
observed with a T-to-C polymorphism in exon 18 of nNOS, designated nNOS
18. Moreover, a significant interaction of the nNOS polymorphisms with
current and/or past cigarette smoking was found (nNOS 18, p = 0.05; nNOS
29, p = 0.04). Levecque et al. (2003) suggested that NOS1 may be a
modifier gene in PD.

Infantile hypertrophic pyloric stenosis (IHPS; 179010), characterized by
enlarged pyloric musculature and gastric outlet obstruction, is
associated with altered expression of NOS1. Saur et al. (2004) studied
molecular mechanisms by which NOS1 gene expression was altered in
pyloric tissues of 16 German infants with IHPS and 9 German controls. In
IHPS patients, quantitative RT-PCR after normalization against
glyceraldehyde-3-phosphate dehydrogenase (GAPD; 138400) showed
significantly decreased expression of total NOS1 mRNA, which affected
predominantly exon 1c. Expression of exon 1f was increased
significantly, indicating a compensatory upregulation of this NOS1 mRNA
variant. DNA samples of 16 IHPS patients and 81 controls were analyzed
for NOS1 exon 1c promoter mutations and SNPs. Sequencing of the 5-prime
flanking region of exon 1c revealed mutations in 3 of 16 IHPS tissues,
whereas 81 controls showed the wildtype sequence exclusively. Carriers
of the A allele of a -84G-A SNP (dbSNP rs41279104) in the exon 1c
promoter region (163731.0001) had increased risk for development of IHPS
(odds ratio, 8.0; 95% CI, 2.5 to 25.6). Reporter gene assays revealed an
unchanged promoter activity for mutations but an approximately 30%
decrease for the A allele of the -84G-A SNP (p less than 0.001). Saur et
al. (2004) interpreted their findings as indicating that genetic
alterations in the NOS1 exon 1c regulatory region influence expression
of the gene and contribute to the pathogenesis of IHPS. In contrast,
Lagerstedt-Robinson et al. (2009) found no association between dbSNP
rs41279104 and infantile hypertrophic pyloric stenosis among 82 Swedish
patients and 80 controls. The frequency of the A allele in the control
group was 29%.

Reif et al. (2006) studied NOS1 as a candidate gene for schizophrenia
(see 181500) and bipolar disorder (125480) because the gene is located
in a major linkage hotspot for both disorders and because nitric oxide
is a promising candidate molecule in the pathogenesis of endogenous
psychosis. Reif et al. (2006) examined 5 NOS1 polymorphisms as well as a
haplotype consisting of 2 functional polymorphisms located in the
transcriptional control region of the gene (G-84A and a VNTR) in 195
chronic schizophrenia patients, 72 bipolar I patients, and 286 controls.
Single-marker association analyses showed that the exon 1c promoter
polymorphism (G-84A) was linked to schizophrenia, whereas synonymous
coding region polymorphisms were not associated with disease. Long
promoter alleles of the repeat polymorphism were associated with less
severe psychopathology. The haplotype was also shown to be significantly
associated with schizophrenia. Reif et al. (2006) suggested that
regulatory polymorphisms of NOS1 contribute to the genetic risk for
schizophrenia.

ANIMAL MODEL

Mice with targeted disruption of neuronal NO synthase display grossly
normal appearance, locomotor activity, breeding, long-term potentiation,
and long-term depression. NOS1-deficient mice are resistant to neural
stroke damage following middle cerebral artery ligation. Nelson et al.
(1995) reported a large increase in aggressive behavior and excessive,
inappropriate sexual behavior in NOS1 'knockout' mice. Initial
observations indicated that male NOS1-deficient mice engaged in chronic
aggressive behavior, not apparent among NOS1-deficient female mice or
wildtype male or female mice housed together. Relevance of the
observations to human behavior was suggested.

In the heart, nitric oxide inhibits L-type calcium channels but
stimulates sarcoplasmic reticulum calcium release, leading to variable
effects on myocardial contractility. Barouch et al. (2002) demonstrated
that spatial confinement of specific nitric oxide synthase isoforms
regulates this process. Endothelial nitric oxide synthase (NOS3)
localizes to caveolae, where compartmentalization with beta-adrenergic
receptors and L-type calcium channels allows nitric oxide to inhibit
beta-adrenergic-induced inotropy. Neuronal nitric oxide synthase (NOS1),
however, is targeted to cardiac sarcoplasmic reticulum. NO stimulation
of sarcoplasmic reticulum calcium release via the ryanodine receptor
(RYR2; 180902) in vitro suggests that NOS1 has an opposite, facilitative
effect on contractility. Barouch et al. (2002) demonstrated that
Nos1-deficient mice have suppressed inotropic response, whereas
Nos3-deficient mice have enhanced contractility, owing to corresponding
changes in sarcoplasmic reticulum calcium release. Both Nos1 -/- and
Nos3 -/- mice developed age-related hypertrophy, although only Nos3 -/-
mice were hypertensive. Nos1/3 -/- double knockout mice had suppressed
beta-adrenergic responses and an additive phenotype of marked
ventricular remodeling. Thus, NOS1 and NOS3 mediate independent, and in
some cases opposite, effects on cardiac structure and function.

Wehling-Henricks et al. (2005) produced dystrophin (300377)-deficient
mdx mice in which there was myocardial expression of a NOS1 transgene.
Expression of the transgene prevented the progressive ventricular
fibrosis of mdx mice and greatly reduced myocarditis.
Electrocardiographs (ECG) of ambulatory mdx mice showed cardiac
abnormalities that were characteristic of DMD patients. All of these ECG
abnormalities in mdx mice were improved or corrected by NOS1 transgene
expression. In addition, defects in mdx cardiac autonomic function,
which were reflected by decreased heart rate variability, were
significantly reduced by NOS1 transgene expression. Wehling-Henricks et
al. (2005) concluded that their findings indicate that increasing NO
production by dystrophic hearts may have therapeutic value.

Hurt et al. (2006) noted that, in addition to the predominant nNos-alpha
isoform, alternative splicing produces catalytically active nNos-beta
and catalytically inactive nNos-gamma. They found that nNos-beta
preserved normal erectile function in mice lacking nNos-alpha, despite a
decrease in stimulus-response characteristics and increased sensitivity
to a NOS inhibitor.

*FIELD* AV
.0001
RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE
NOS1, -84G-A (dbSNP rs41279104)

This variant, formerly titled PYLORIC STENOSIS, INFANTILE HYPERTROPHIC,
SUSCEPTIBILITY TO, has been reclassified based on the findings of
Lagerstedt-Robinson et al. (2009).

In a study of 16 German patients with infantile hypertrophic pyloric
stenosis (179010) and 81 German controls, Saur et al. (2004) found that
carriers of the A allele of a -84G-A SNP in the exon 1c promoter of the
NOS1 gene had increased risk for development of IHPS (odds ratio, 8.0;
95% CI, 2.5 to 25.6). Reporter gene assays revealed an approximately 30%
decrease for the A allele of the -84G-A SNP (P less than 0.001).

In contrast, Lagerstedt-Robinson et al. (2009) found no association
between dbSNP rs41279104 and infantile hypertrophic pyloric stenosis
among 82 Swedish patients and 80 controls. The frequency of the A allele
in the control group was 29%.

*FIELD* RF
1. Barouch, L. A.; Harrison, R. W.; Skaf, M. W.; Rosas, G. O.; Cappola,
T. P.; Kobeissi, Z. A.; Hobai, I. A.; Lemmon, C. A.; Burnett, A. L.;
O'Rourke, B.; Rodriguez, E. R.; Huang, P. L.; Lima, J. A. C.; Berkowitz,
D. E.; Hare, J. M.: Nitric oxide regulates the heart by spatial confinement
of nitric oxide synthase isoforms. Nature 416: 337-340, 2002.

2. Bredt, D. S.; Hwang, P. M.; Glatt, C. E.; Lowenstein, C.; Reed,
R. R.; Snyder, S. H.: Cloned and expressed nitric oxide synthase
structurally resembles cytochrome P-450 reductase. Nature 351: 714-718,
1991.

3. Brenman, J. E.; Chao, D. S.; Xia, H.; Aldape, K.; Bredt, D. S.
: Nitric oxide synthase complexed with dystrophin and absent from
skeletal muscle sarcolemma in Duchenne muscular dystrophy. Cell 82:
743-752, 1995.

4. Burnett, A. L.; Lowenstein, C. J.; Bredt, D. S.; Chang, T. S. K.;
Snyder, S. H.: Nitric oxide: a physiologic mediator of penile erection. Science 257:
401-403, 1992.

5. Day, B. J.; Patel, M.; Calavetta, L.; Chang, L.-Y.; Stamler, J.
S.: A mechanism of paraquat toxicity involving nitric oxide synthase. Proc.
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6. Deans, Z.; Dawson, S. J.; Xie, J.; Young, A. P.; Wallace, D.; Latchman,
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*FIELD* CN
Cassandra L. Kniffin - updated: 8/3/2011
Ada Hamosh - updated: 1/9/2009
George E. Tiller - updated: 11/14/2008
John Logan Black, III - updated: 7/11/2006
Patricia A. Hartz - updated: 3/23/2006
Patricia A. Hartz - updated: 12/16/2005
Marla J. F. O'Neill - updated: 4/25/2005
George E. Tiller - updated: 10/27/2004
Victor A. McKusick - updated: 5/12/2004
Cassandra L. Kniffin - updated: 6/6/2003
Patricia A. Hartz - updated: 3/10/2003
Patricia A. Hartz -updated: 8/23/2002
Ada Hamosh - updated: 3/26/2002
Victor A. McKusick - updated: 1/16/2001
Ada Hamosh - updated: 8/9/2000
Victor A. McKusick - updated: 11/10/1999
Victor A. McKusick - updated: 12/18/1998
Jennifer P. Macke - updated: 8/11/1997

*FIELD* CD
Victor A. McKusick: 8/19/1992

*FIELD* ED
terry: 03/15/2013
alopez: 8/18/2011
ckniffin: 8/3/2011
wwang: 6/18/2010
ckniffin: 6/14/2010
alopez: 1/12/2009
terry: 1/9/2009
wwang: 11/14/2008
alopez: 6/11/2008
carol: 7/11/2006
mgross: 3/29/2006
terry: 3/23/2006
wwang: 1/24/2006
wwang: 12/16/2005
wwang: 4/29/2005
wwang: 4/27/2005
terry: 4/25/2005
terry: 3/16/2005
tkritzer: 10/27/2004
tkritzer: 5/19/2004
terry: 5/12/2004
carol: 6/12/2003
ckniffin: 6/6/2003
mgross: 3/12/2003
terry: 3/10/2003
mgross: 8/23/2002
alopez: 3/26/2002
terry: 3/26/2002
alopez: 3/13/2002
mcapotos: 1/23/2001
terry: 1/16/2001
alopez: 8/9/2000
terry: 8/9/2000
alopez: 11/19/1999
terry: 11/10/1999
carol: 12/29/1998
terry: 12/18/1998
dholmes: 6/1/1998
alopez: 10/7/1997
alopez: 8/11/1997
mark: 2/19/1996
terry: 2/15/1996
terry: 11/17/1995
carol: 3/3/1995
carol: 10/1/1993
carol: 9/21/1993
carol: 9/13/1993
carol: 11/5/1992