ID   SCNNA_MOUSE             Reviewed;         699 AA.
AC   Q61180; Q9WU37;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-DEC-2000, sequence version 2.
DT   27-MAR-2024, entry version 175.
DE   RecName: Full=Amiloride-sensitive sodium channel subunit alpha;
DE   AltName: Full=Alpha-NaCH;
DE   AltName: Full=Epithelial Na(+) channel subunit alpha;
DE            Short=Alpha-ENaC;
DE   AltName: Full=Nonvoltage-gated sodium channel 1 subunit alpha;
DE   AltName: Full=SCNEA;
GN   Name=Scnn1a;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, SUBUNIT, AND TISSUE SPECIFICITY.
RC   STRAIN=C57BL/6J; TISSUE=Kidney;
RX   PubMed=10409305; DOI=10.1152/ajprenal.1999.277.1.f121;
RA   Ahn Y.J., Brooker D.R., Kosari F., Harte B.J., Li J., Mackler S.A.,
RA   Kleyman T.R.;
RT   "Cloning and functional expression of the mouse epithelial sodium
RT   channel.";
RL   Am. J. Physiol. 277:F121-F129(1999).
RN   [2]
RP   PROTEIN SEQUENCE OF 432-437, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC   STRAIN=OF1; TISSUE=Hippocampus;
RA   Lubec G., Sunyer B., Chen W.-Q.;
RL   Submitted (JAN-2009) to UniProtKB.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 445-558.
RC   STRAIN=CD-1; TISSUE=Kidney;
RX   PubMed=9284273; DOI=10.1203/00006450-199709000-00013;
RA   Dagenais A., Kothary R., Berthiaume Y.;
RT   "The alpha subunit of the epithelial sodium channel in the mouse:
RT   developmental regulation of its expression.";
RL   Pediatr. Res. 42:327-334(1997).
RN   [4]
RP   INTERACTION WITH NEDD4 AND NEDD4L.
RX   PubMed=11244092; DOI=10.1074/jbc.c000906200;
RA   Harvey K.F., Dinudom A., Cook D.I., Kumar S.;
RT   "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial
RT   sodium channel.";
RL   J. Biol. Chem. 276:8597-8601(2001).
RN   [5]
RP   INTERACTION WITH NEDD4L.
RX   PubMed=12424229; DOI=10.1096/fj.02-0497fje;
RA   Fotia A.B., Dinudom A., Shearwin K.E., Koch J.-P., Korbmacher C.,
RA   Cook D.I., Kumar S.;
RT   "The role of individual Nedd4-2 (KIAA0439) WW domains in binding and
RT   regulating epithelial sodium channels.";
RL   FASEB J. 17:70-72(2003).
RN   [6]
RP   INTERACTION WITH NEDD4 AND NEDD4L.
RX   PubMed=15123669; DOI=10.1074/jbc.m402820200;
RA   Fotia A.B., Ekberg J., Adams D.J., Cook D.I., Poronnik P., Kumar S.;
RT   "Regulation of neuronal voltage-gated sodium channels by the ubiquitin-
RT   protein ligases Nedd4 and Nedd4-2.";
RL   J. Biol. Chem. 279:28930-28935(2004).
RN   [7]
RP   ACTIVITY REGULATION.
RX   PubMed=20525693; DOI=10.1074/jbc.m110.103432;
RA   Heise C.J., Xu B.E., Deaton S.L., Cha S.K., Cheng C.J., Earnest S.,
RA   Sengupta S., Juang Y.C., Stippec S., Xu Y., Zhao Y., Huang C.L., Cobb M.H.;
RT   "Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium
RT   channel are regulated by multiple with no lysine (WNK) family members.";
RL   J. Biol. Chem. 285:25161-25167(2010).
RN   [8]
RP   TISSUE SPECIFICITY.
RX   PubMed=22207244; DOI=10.1007/s00418-011-0904-1;
RA   Enuka Y., Hanukoglu I., Edelheit O., Vaknine H., Hanukoglu A.;
RT   "Epithelial sodium channels (ENaC) are uniformly distributed on motile
RT   cilia in the oviduct and the respiratory airways.";
RL   Histochem. Cell Biol. 137:339-353(2012).
RN   [9]
RP   TISSUE SPECIFICITY.
RX   PubMed=30659401; DOI=10.1007/s10735-019-09813-3;
RA   Sharma S., Hanukoglu I.;
RT   "Mapping the sites of localization of epithelial sodium channel (ENaC) and
RT   CFTR in segments of the mammalian epididymis.";
RL   J. Mol. Histol. 50:141-154(2019).
CC   -!- FUNCTION: Sodium permeable non-voltage-sensitive ion channel inhibited
CC       by the diuretic amiloride. Mediates the electrodiffusion of the luminal
CC       sodium (and water, which follows osmotically) through the apical
CC       membrane of epithelial cells. Plays an essential role in electrolyte
CC       and blood pressure homeostasis, but also in airway surface liquid
CC       homeostasis, which is important for proper clearance of mucus. Controls
CC       the reabsorption of sodium in kidney, colon, lung and eccrine sweat
CC       glands. Also plays a role in taste perception.
CC       {ECO:0000269|PubMed:10409305}.
CC   -!- ACTIVITY REGULATION: Activated by WNK1, WNK2, WNK3 and WNK4.
CC       {ECO:0000269|PubMed:20525693}.
CC   -!- SUBUNIT: Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a
CC       gamma/SCNN1G subunit. An additional delta/SCNN1D subunit exists only in
CC       some organisms and can replace the alpha/SCNN1A subunit to form an
CC       alternative channel with specific properties (Probable). Interacts with
CC       NEDD4 (via WW domains) (PubMed:11244092, PubMed:15123669). Interacts
CC       with NEDD4L (via WW domains) (PubMed:11244092, PubMed:12424229,
CC       PubMed:15123669). Interacts with WWP1 (via WW domains). Interacts with
CC       WWP2 (via WW domains). Interacts with the full-length immature form of
CC       PCSK9 (pro-PCSK9). {ECO:0000250|UniProtKB:P37088,
CC       ECO:0000269|PubMed:11244092, ECO:0000269|PubMed:12424229,
CC       ECO:0000269|PubMed:15123669, ECO:0000305, ECO:0000305|PubMed:10409305}.
CC   -!- SUBCELLULAR LOCATION: Apical cell membrane
CC       {ECO:0000250|UniProtKB:P37089}; Multi-pass membrane protein
CC       {ECO:0000250|UniProtKB:P37089}. Cell projection, cilium
CC       {ECO:0000250|UniProtKB:P37088}. Cytoplasmic granule
CC       {ECO:0000250|UniProtKB:P37088}. Cytoplasm
CC       {ECO:0000250|UniProtKB:P37088}. Cytoplasmic vesicle, secretory vesicle,
CC       acrosome {ECO:0000250|UniProtKB:P37089}. Cell projection, cilium,
CC       flagellum {ECO:0000250|UniProtKB:P37089}. Note=In the oviduct and
CC       bronchus, located on cilia in multi-ciliated cells. In endometrial non-
CC       ciliated epithelial cells, restricted to apical surfaces. In epidermis,
CC       located nearly uniformly in the cytoplasm in a granular distribution.
CC       In sebaceous glands, observed only in the cytoplasmic space in between
CC       the lipid vesicles. In eccrine sweat glands, mainly located at the
CC       apical surface of the cells facing the lumen. In skin, in arrector pili
CC       muscle cells and in adipocytes, located in the cytoplasm and
CC       colocalized with actin fibers. In spermatogonia, spermatocytes and
CC       round spermatids, located in the cytoplasm. Prior to spermiation,
CC       location shifts from the cytoplasm to the spermatid tail. In
CC       spermatozoa, localizes at the acrosome and the central region of the
CC       sperm flagellum. {ECO:0000250|UniProtKB:P37088,
CC       ECO:0000250|UniProtKB:P37089}.
CC   -!- TISSUE SPECIFICITY: Expressed in kidney (at protein level)
CC       (PubMed:22207244). Expressed in lung (at protein level)
CC       (PubMed:22207244, PubMed:30659401). Expressed in the epididymis (at
CC       protein level) (PubMed:30659401). In the caput and corpus regions of
CC       the epididymis, expressed uniformly on the luminal and basal surfaces
CC       of the ducts and in the sperm in the duct lumen (PubMed:30659401). Also
CC       expressed in distal colon and, at low levels, in liver
CC       (PubMed:10409305). {ECO:0000269|PubMed:10409305,
CC       ECO:0000269|PubMed:22207244, ECO:0000269|PubMed:30659401}.
CC   -!- PTM: Ubiquitinated; this targets individual subunits for endocytosis
CC       and proteasome-mediated degradation. {ECO:0000250|UniProtKB:P37089}.
CC   -!- PTM: ENaC cleavage by furin, and subsequently by prostasin (PRSS8),
CC       leads to a stepwise increase in the open probability of the channel as
CC       a result of release of the alpha and gamma subunit inhibitory tracts,
CC       respectively. Interaction of ENaC subunit SCNN1B with BPIFA1 protects
CC       ENaC against proteolytic activation. {ECO:0000250|UniProtKB:P37088}.
CC   -!- PTM: N-glycosylated. {ECO:0000250|UniProtKB:P37089}.
CC   -!- SIMILARITY: Belongs to the amiloride-sensitive sodium channel
CC       (TC 1.A.6) family. SCNN1A subfamily. {ECO:0000305}.
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DR   EMBL; AF112185; AAD21244.1; -; mRNA.
DR   EMBL; U52006; AAA97412.1; -; mRNA.
DR   CCDS; CCDS39641.2; -.
DR   RefSeq; NP_035454.2; NM_011324.2.
DR   AlphaFoldDB; Q61180; -.
DR   SMR; Q61180; -.
DR   BioGRID; 203105; 7.
DR   ComplexPortal; CPX-315; Amiloride-sensitive sodium channel complex, alpha-beta-gamma.
DR   DIP; DIP-40889N; -.
DR   IntAct; Q61180; 1.
DR   STRING; 10090.ENSMUSP00000080164; -.
DR   BindingDB; Q61180; -.
DR   ChEMBL; CHEMBL3608200; -.
DR   GuidetoPHARMACOLOGY; 738; -.
DR   iPTMnet; Q61180; -.
DR   PhosphoSitePlus; Q61180; -.
DR   PaxDb; 10090-ENSMUSP00000080164; -.
DR   ProteomicsDB; 255363; -.
DR   DNASU; 20276; -.
DR   Ensembl; ENSMUST00000081440.14; ENSMUSP00000080164.9; ENSMUSG00000030340.17.
DR   GeneID; 20276; -.
DR   KEGG; mmu:20276; -.
DR   AGR; MGI:101782; -.
DR   CTD; 6337; -.
DR   MGI; MGI:101782; Scnn1a.
DR   eggNOG; KOG4294; Eukaryota.
DR   GeneTree; ENSGT00940000160952; -.
DR   InParanoid; Q61180; -.
DR   OMA; MRQCKQE; -.
DR   OrthoDB; 5344287at2759; -.
DR   PhylomeDB; Q61180; -.
DR   Reactome; R-MMU-2672351; Stimuli-sensing channels.
DR   Reactome; R-MMU-9730628; Sensory perception of salty taste.
DR   BioGRID-ORCS; 20276; 6 hits in 78 CRISPR screens.
DR   ChiTaRS; Scnn1a; mouse.
DR   PRO; PR:Q61180; -.
DR   Proteomes; UP000000589; Chromosome 6.
DR   RNAct; Q61180; Protein.
DR   GO; GO:0001669; C:acrosomal vesicle; ISS:UniProtKB.
DR   GO; GO:0016324; C:apical plasma membrane; ISS:UniProtKB.
DR   GO; GO:0060170; C:ciliary membrane; ISS:UniProtKB.
DR   GO; GO:0030864; C:cortical actin cytoskeleton; ISO:MGI.
DR   GO; GO:0005737; C:cytoplasm; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; IDA:MGI.
DR   GO; GO:0009897; C:external side of plasma membrane; IDA:MGI.
DR   GO; GO:0070062; C:extracellular exosome; ISO:MGI.
DR   GO; GO:0016020; C:membrane; IDA:MGI.
DR   GO; GO:0031514; C:motile cilium; ISS:UniProtKB.
DR   GO; GO:0005886; C:plasma membrane; ISS:UniProtKB.
DR   GO; GO:0034706; C:sodium channel complex; IDA:MGI.
DR   GO; GO:0097228; C:sperm principal piece; ISS:UniProtKB.
DR   GO; GO:0003779; F:actin binding; ISO:MGI.
DR   GO; GO:0015280; F:ligand-gated sodium channel activity; IDA:MGI.
DR   GO; GO:0050699; F:WW domain binding; IPI:MGI.
DR   GO; GO:0071468; P:cellular response to acidic pH; ISO:MGI.
DR   GO; GO:1904045; P:cellular response to aldosterone; IDA:MGI.
DR   GO; GO:1904117; P:cellular response to vasopressin; NAS:ComplexPortal.
DR   GO; GO:0006883; P:intracellular sodium ion homeostasis; IDA:ComplexPortal.
DR   GO; GO:0050891; P:multicellular organismal-level water homeostasis; ISS:UniProtKB.
DR   GO; GO:0008217; P:regulation of blood pressure; NAS:ComplexPortal.
DR   GO; GO:0050878; P:regulation of body fluid levels; ISO:MGI.
DR   GO; GO:0050914; P:sensory perception of salty taste; NAS:ComplexPortal.
DR   GO; GO:0050915; P:sensory perception of sour taste; NAS:ComplexPortal.
DR   GO; GO:0055078; P:sodium ion homeostasis; ISS:UniProtKB.
DR   GO; GO:0098719; P:sodium ion import across plasma membrane; IDA:ComplexPortal.
DR   GO; GO:0035725; P:sodium ion transmembrane transport; ISO:MGI.
DR   GO; GO:0006814; P:sodium ion transport; IDA:MGI.
DR   Gene3D; 2.60.470.10; Acid-sensing ion channels like domains; 1.
DR   Gene3D; 1.10.287.770; YojJ-like; 1.
DR   InterPro; IPR001873; ENaC.
DR   InterPro; IPR004724; ENaC_chordates.
DR   InterPro; IPR020903; ENaC_CS.
DR   NCBIfam; TIGR00859; ENaC; 1.
DR   PANTHER; PTHR11690:SF124; AMILORIDE-SENSITIVE SODIUM CHANNEL SUBUNIT ALPHA; 1.
DR   PANTHER; PTHR11690; AMILORIDE-SENSITIVE SODIUM CHANNEL-RELATED; 1.
DR   Pfam; PF00858; ASC; 1.
DR   PRINTS; PR01078; AMINACHANNEL.
DR   PROSITE; PS01206; ASC; 1.
PE   1: Evidence at protein level;
KW   Cell membrane; Cell projection; Cilium; Cytoplasm; Cytoplasmic vesicle;
KW   Direct protein sequencing; Flagellum; Glycoprotein; Ion channel;
KW   Ion transport; Membrane; Reference proteome; Sensory transduction; Sodium;
KW   Sodium channel; Sodium transport; Taste; Transmembrane;
KW   Transmembrane helix; Transport; Ubl conjugation.
FT   CHAIN           1..699
FT                   /note="Amiloride-sensitive sodium channel subunit alpha"
FT                   /id="PRO_0000181262"
FT   TOPO_DOM        1..110
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P37089"
FT   TRANSMEM        111..131
FT                   /note="Helical; Name=1"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        132..589
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000250|UniProtKB:P37089"
FT   TRANSMEM        590..610
FT                   /note="Helical; Name=2"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        611..699
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000250|UniProtKB:P37089"
FT   REGION          1..71
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          211..244
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          637..699
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        46..71
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        645..669
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   CONFLICT        445
FT                   /note="H -> R (in Ref. 3; AAA97412)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        555..557
FT                   /note="FKE -> YKH (in Ref. 3; AAA97412)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   699 AA;  78893 MW;  5B083BE8769B017A CRC64;
     MLDHTRAPEL NLDLDLDVSN SPKGSMKGNN FKEQDLCPPL PMQGLGKGDK REEQALGPEP
     SEPRQPTEEE EALIEFHRSY RELFQFFCNN TTIHGAIRLV CSKHNRMKTA FWAVLWLCTF
     GMMYWQFALL FEEYFSYPVS LNINLNSDKL VFPAVTVCTL NPYRYTEIKE DLEELDRITE
     QTLFDLYKYN SSYTRQAGGR RRSTRDLRGA LPHPLQRLRT PPPPNPARSA RSASSSVRDN
     NPQVDRKDWK IGFQLCNQNK SDCFYQTYSS GVDAVREWYR FHYINILSRL PDTSPALEEE
     ALGSFIFTCR FNQAPCNQAN YSQFHHPMYG NCYTFNNKNN SNLWMSSMPG VNNGLSLTLR
     TEQNDFIPLL STVTGARVMV HGQDEPAFMD DGGFNVRPGV ETSISMRKEA LDSLGGNYGD
     CTENGSDVPV KNLYPSKYTQ QVCIHSCFQE NMIKKCGCAY IFYPKPKGVE FCDYLKQSSW
     GYCYYKLQAA FSLDSLGCFS KCRKPCSVTN YKLSAGYSRW PSVKSQDWIF EMLSLQNNYT
     INNKRNGVAK LNIFFKELNY KTNSESPSVT MVSLLSNLGS QWSLWFGSSV LSVVEMAELI
     FDLLVITLIM LLHRFRSRYW SPGRGARGAR EVASTPASSF PSRFCPHPTS PPPSLPQQGT
     TPPLALTAPP PAYATLGPSA SPLDSAVPGS SACAPAMAL
//