SCNNA_RAT
ID SCNNA_RAT Reviewed; 698 AA.
AC P37089; Q64593; Q9QUI4;
DT 01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
DT 01-DEC-2000, sequence version 2.
DT 03-AUG-2022, entry version 162.
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; Synonyms=Renac;
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND FUNCTION.
RC STRAIN=Wistar; TISSUE=Distal colon;
RX PubMed=8382172; DOI=10.1016/0014-5793(93)81336-x;
RA Lingueglia E., Voilley N., Waldmann R., Lazdunski M., Barbry P.;
RT "Expression cloning of an epithelial amiloride-sensitive Na+ channel. A new
RT channel type with homologies to Caenorhabditis elegans degenerins.";
RL FEBS Lett. 318:95-99(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=Sprague-Dawley; TISSUE=Colon epithelium;
RX PubMed=8381523; DOI=10.1038/361467a0;
RA Canessa C.M., Horisberger J.-D., Rossier B.C.;
RT "Epithelial sodium channel related to proteins involved in
RT neurodegeneration.";
RL Nature 361:467-470(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC STRAIN=SHRSP, and Wistar Kyoto; TISSUE=Kidney;
RX PubMed=9039092; DOI=10.1161/01.hyp.29.1.131;
RA Kreutz R., Struk B., Rubattu S., Hubner N., Szpirer J., Szpirer C.,
RA Ganten D., Lindpaintner K.;
RT "Role of the alpha-, beta-, and gamma-subunits of epithelial sodium channel
RT in a model of polygenic hypertension.";
RL Hypertension 29:131-136(1997).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 1-76.
RC STRAIN=Wistar;
RX PubMed=10226074; DOI=10.1165/ajrcmb.20.5.3382;
RA Otulakowski G., Rafii B., Bremner H.R., O'Brodovich H.;
RT "Structure and hormone responsiveness of the gene encoding the alpha-
RT subunit of the rat amiloride-sensitive epithelial sodium channel.";
RL Am. J. Respir. Cell Mol. Biol. 20:1028-1040(1999).
RN [5]
RP TOPOLOGY, AND GLYCOSYLATION AT ASN-190; ASN-259; ASN-320; ASN-339; ASN-424
RP AND ASN-538.
RX PubMed=7929098; DOI=10.1016/s0021-9258(19)51094-8;
RA Snyder P.M., McDonald F.J., Stokes J.B., Welsh M.J.;
RT "Membrane topology of the amiloride-sensitive epithelial sodium channel.";
RL J. Biol. Chem. 269:24379-24383(1994).
RN [6]
RP TOPOLOGY.
RX PubMed=8175716; DOI=10.1016/s0021-9258(18)99972-2;
RA Renard S., Lingueglia E., Voilley N., Lazdunski M., Barbry P.;
RT "Biochemical analysis of the membrane topology of the amiloride-sensitive
RT Na+ channel.";
RL J. Biol. Chem. 269:12981-12986(1994).
RN [7]
RP MUTAGENESIS OF SER-588 AND SER-592.
RX PubMed=7744818; DOI=10.1074/jbc.270.20.11735;
RA Waldmann R., Champigny G., Lazdunski M.;
RT "Functional degenerin-containing chimeras identify residues essential for
RT amiloride-sensitive Na+ channel function.";
RL J. Biol. Chem. 270:11735-11737(1995).
RN [8]
RP FUNCTION, INTERACTION WITH SCNN1B AND SCNN1G, SUBCELLULAR LOCATION, AND
RP TOPOLOGY.
RX PubMed=9118951; DOI=10.1093/emboj/16.5.899;
RA Gruender S., Firsov D., Chang S.S., Jaeger N.F., Gautschi I., Schild L.,
RA Lifton R.P., Rossier B.C.;
RT "A mutation causing pseudohypoaldosteronism type 1 identifies a conserved
RT glycine that is involved in the gating of the epithelial sodium channel.";
RL EMBO J. 16:899-907(1997).
RN [9]
RP UBIQUITINATION.
RX PubMed=9351815; DOI=10.1093/emboj/16.21.6325;
RA Staub O., Gautschi I., Ishikawa T., Breitschopf K., Ciechanover A.,
RA Schild L., Rotin D.;
RT "Regulation of stability and function of the epithelial Na+ channel (ENaC)
RT by ubiquitination.";
RL EMBO J. 16:6325-6336(1997).
RN [10]
RP SUBCELLULAR LOCATION.
RX PubMed=11352848; DOI=10.1152/ajprenal.2001.280.6.f1093;
RA Hager H., Kwon T.H., Vinnikova A.K., Masilamani S., Brooks H.L.,
RA Frokiaer J., Knepper M.A., Nielsen S.;
RT "Immunocytochemical and immunoelectron microscopic localization of alpha-,
RT beta-, and gamma-ENaC in rat kidney.";
RL Am. J. Physiol. 280:F1093-F1106(2001).
RN [11]
RP INTERACTION WITH NEDD4.
RX PubMed=11323714; DOI=10.1038/87562;
RA Kanelis V., Rotin D., Forman-Kay J.D.;
RT "Solution structure of a Nedd4 WW domain-ENaC peptide complex.";
RL Nat. Struct. Biol. 8:407-412(2001).
RN [12]
RP SUBCELLULAR LOCATION, AND GLYCOSYLATION.
RX PubMed=11773057; DOI=10.1074/jbc.m110904200;
RA Hanwell D., Ishikawa T., Saleki R., Rotin D.;
RT "Trafficking and cell surface stability of the epithelial Na+ channel
RT expressed in epithelial Madin-Darby canine kidney cells.";
RL J. Biol. Chem. 277:9772-9779(2002).
RN [13]
RP INTERACTION WITH NEDD4L.
RX PubMed=14556380; DOI=10.1016/s1631-0691(03)00154-9;
RA Malbert-Colas L., Nicolas G., Galand C., Lecomte M.-C., Dhermy D.;
RT "Identification of new partners of the epithelial sodium channel alpha
RT subunit.";
RL C. R. Biol. 326:615-624(2003).
RN [14]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=29453757; DOI=10.1007/s10735-018-9759-2;
RA Sharma S., Hanukoglu A., Hanukoglu I.;
RT "Localization of epithelial sodium channel (ENaC) and CFTR in the germinal
RT epithelium of the testis, Sertoli cells, and spermatozoa.";
RL J. Mol. Histol. 49:195-208(2018).
CC -!- FUNCTION: Sodium permeable non-voltage-sensitive ion channel inhibited
CC by the diuretic amiloride (PubMed:9118951). Mediates the
CC electrodiffusion of the luminal sodium (and water, which follows
CC osmotically) through the apical membrane of epithelial cells
CC (PubMed:8382172, PubMed:9118951). Plays an essential role in
CC electrolyte and blood pressure homeostasis, but also in airway surface
CC liquid homeostasis, which is important for proper clearance of mucus.
CC Controls the reabsorption of sodium in kidney, colon, lung and eccrine
CC sweat glands. Also plays a role in taste perception (By similarity).
CC {ECO:0000250|UniProtKB:P37088, ECO:0000269|PubMed:8382172}.
CC -!- ACTIVITY REGULATION: Activated by WNK1, WNK2, WNK3 and WNK4.
CC {ECO:0000250|UniProtKB:Q61180}.
CC -!- SUBUNIT: Heterotrimer containing an alpha/SCNN1A, a beta/SCNN1B and a
CC gamma/SCNN1G subunit (PubMed:9118951). An additional delta/SCNN1D
CC subunit exists only in some organisms and can replace the alpha/SCNN1A
CC subunit to form an alternative channel with specific properties (By
CC similarity). Interacts with NEDD4 (via WW domains) (PubMed:11323714).
CC Interacts with NEDD4L (via WW domains) (PubMed:14556380). Interacts
CC with WWP1 (via WW domains) (By similarity). Interacts with WWP2 (via WW
CC domains) (By similarity). Interacts with the full-length immature form
CC of PCSK9 (pro-PCSK9) (By similarity). {ECO:0000250|UniProtKB:P37088,
CC ECO:0000250|UniProtKB:Q61180, ECO:0000269|PubMed:11323714,
CC ECO:0000269|PubMed:14556380, ECO:0000269|PubMed:9118951}.
CC -!- SUBCELLULAR LOCATION: Apical cell membrane
CC {ECO:0000269|PubMed:11352848, ECO:0000269|PubMed:11773057,
CC ECO:0000269|PubMed:9118951}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:7929098, ECO:0000269|PubMed:8175716}. Cell
CC projection, cilium {ECO:0000250|UniProtKB:P37088}. Cytoplasmic granule
CC {ECO:0000250|UniProtKB:P37088}. Cytoplasm
CC {ECO:0000269|PubMed:29453757}. Cytoplasmic vesicle, secretory vesicle,
CC acrosome {ECO:0000269|PubMed:29453757}. Cell projection, cilium,
CC flagellum {ECO:0000269|PubMed:29453757}. Note=In multi-ciliated cells,
CC located on cilia. In non-ciliated epithelial cells, restricted to
CC apical surfaces. In epidermis, located nearly uniformly in the
CC cytoplasm in a granular distribution. In sebaceous glands, observed
CC only in the cytoplasmic space in between the lipid vesicles. In eccrine
CC sweat glands, mainly located at the apical surface of the cells facing
CC the lumen (By similarity). In skin, in arrector pili muscle cells and
CC in adipocytes, located in the cytoplasm and colocalized with actin
CC fibers (By similarity). In spermatogonia, spermatocytes and round
CC spermatids, located in the cytoplasm (PubMed:29453757). Prior to
CC spermiation, location shifts from the cytoplasm to the spermatid tail
CC (PubMed:29453757). In spermatozoa, localizes at the acrosome and the
CC central region of the sperm flagellum (PubMed:29453757).
CC {ECO:0000250|UniProtKB:P37088, ECO:0000269|PubMed:11773057,
CC ECO:0000269|PubMed:29453757}.
CC -!- TISSUE SPECIFICITY: Detected in kidney, lung and testis (at protein
CC level). In the testis, detected within the seminiferous tubules but not
CC in the interstitial cells (at protein level).
CC {ECO:0000269|PubMed:29453757}.
CC -!- PTM: Ubiquitinated; this targets individual subunits for endocytosis
CC and proteasome-mediated degradation. {ECO:0000269|PubMed:9351815}.
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:0000269|PubMed:11773057}.
CC -!- SIMILARITY: Belongs to the amiloride-sensitive sodium channel (TC
CC 1.A.6) family. SCNN1A subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA49916.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
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DR EMBL; X70521; CAA49916.1; ALT_INIT; mRNA.
DR EMBL; X70497; CAA49905.1; -; mRNA.
DR EMBL; U54699; AAB61156.1; -; mRNA.
DR EMBL; U54700; AAB61157.1; -; mRNA.
DR EMBL; AF081783; AAD16017.1; -; Genomic_DNA.
DR EMBL; AF082073; AAD16026.1; -; mRNA.
DR PIR; S29499; S29499.
DR RefSeq; NP_113736.1; NM_031548.2.
DR AlphaFoldDB; P37089; -.
DR SMR; P37089; -.
DR BioGRID; 247193; 2.
DR ComplexPortal; CPX-314; Amiloride-sensitive sodium channel complex, alpha-beta-gamma.
DR DIP; DIP-61308N; -.
DR IntAct; P37089; 3.
DR STRING; 10116.ENSRNOP00000061813; -.
DR GlyGen; P37089; 6 sites.
DR iPTMnet; P37089; -.
DR PhosphoSitePlus; P37089; -.
DR PaxDb; P37089; -.
DR PRIDE; P37089; -.
DR GeneID; 25122; -.
DR KEGG; rno:25122; -.
DR UCSC; RGD:3639; rat.
DR CTD; 6337; -.
DR RGD; 3639; Scnn1a.
DR eggNOG; KOG4294; Eukaryota.
DR InParanoid; P37089; -.
DR OMA; EKTRQCK; -.
DR OrthoDB; 686369at2759; -.
DR PhylomeDB; P37089; -.
DR Reactome; R-RNO-2672351; Stimuli-sensing channels.
DR Reactome; R-RNO-9730628; Sensory perception of salty taste.
DR PRO; PR:P37089; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0001669; C:acrosomal vesicle; IDA:UniProtKB.
DR GO; GO:0016324; C:apical plasma membrane; IDA:UniProtKB.
DR GO; GO:0060170; C:ciliary membrane; ISS:UniProtKB.
DR GO; GO:0030864; C:cortical actin cytoskeleton; IDA:RGD.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; ISO:RGD.
DR GO; GO:0009897; C:external side of plasma membrane; ISO:RGD.
DR GO; GO:0070062; C:extracellular exosome; ISO:RGD.
DR GO; GO:0016021; C:integral component of membrane; ISO:RGD.
DR GO; GO:0005887; C:integral component of plasma membrane; ISS:UniProtKB.
DR GO; GO:0016020; C:membrane; ISO:RGD.
DR GO; GO:0031514; C:motile cilium; ISS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IC:ComplexPortal.
DR GO; GO:0034706; C:sodium channel complex; IPI:ComplexPortal.
DR GO; GO:0097228; C:sperm principal piece; IDA:UniProtKB.
DR GO; GO:0003779; F:actin binding; IDA:RGD.
DR GO; GO:0015280; F:ligand-gated sodium channel activity; IDA:RGD.
DR GO; GO:0050699; F:WW domain binding; IPI:RGD.
DR GO; GO:0071468; P:cellular response to acidic pH; ISO:RGD.
DR GO; GO:1904045; P:cellular response to aldosterone; ISO:RGD.
DR GO; GO:0036254; P:cellular response to amiloride; IDA:ComplexPortal.
DR GO; GO:1904117; P:cellular response to vasopressin; IC:ComplexPortal.
DR GO; GO:0006883; P:cellular sodium ion homeostasis; IDA:ComplexPortal.
DR GO; GO:0050891; P:multicellular organismal water homeostasis; ISS:UniProtKB.
DR GO; GO:0008217; P:regulation of blood pressure; TAS:RGD.
DR GO; GO:0050878; P:regulation of body fluid levels; IMP:RGD.
DR GO; GO:0050914; P:sensory perception of salty taste; IC:ComplexPortal.
DR GO; GO:0050915; P:sensory perception of sour taste; IC: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; ISS:UniProtKB.
DR GO; GO:0006814; P:sodium ion transport; IDA:RGD.
DR InterPro; IPR001873; ENaC.
DR InterPro; IPR004724; ENaC_chordates.
DR InterPro; IPR020903; ENaC_CS.
DR PANTHER; PTHR11690; PTHR11690; 1.
DR Pfam; PF00858; ASC; 1.
DR PRINTS; PR01078; AMINACHANNEL.
DR TIGRFAMs; TIGR00859; ENaC; 1.
DR PROSITE; PS01206; ASC; 1.
PE 1: Evidence at protein level;
KW Cell membrane; Cell projection; Cilium; Cytoplasm; Cytoplasmic vesicle;
KW Flagellum; Glycoprotein; Ion channel; Ion transport; Membrane;
KW Reference proteome; Sensory transduction; Sodium; Sodium channel;
KW Sodium transport; Taste; Transmembrane; Transmembrane helix; Transport;
KW Ubl conjugation.
FT CHAIN 1..698
FT /note="Amiloride-sensitive sodium channel subunit alpha"
FT /id="PRO_0000181264"
FT TOPO_DOM 1..110
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:7929098,
FT ECO:0000269|PubMed:8175716"
FT TRANSMEM 111..131
FT /note="Helical; Name=1"
FT /evidence="ECO:0000255"
FT TOPO_DOM 132..589
FT /note="Extracellular"
FT /evidence="ECO:0000269|PubMed:7929098,
FT ECO:0000269|PubMed:8175716, ECO:0000269|PubMed:9118951"
FT TRANSMEM 590..610
FT /note="Helical; Name=2"
FT /evidence="ECO:0000255"
FT TOPO_DOM 611..698
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:7929098,
FT ECO:0000269|PubMed:8175716"
FT REGION 1..70
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 213..243
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 637..663
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 645..663
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT CARBOHYD 190
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:7929098"
FT CARBOHYD 259
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:7929098"
FT CARBOHYD 320
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:7929098"
FT CARBOHYD 339
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:7929098"
FT CARBOHYD 424
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:7929098"
FT CARBOHYD 538
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:7929098"
FT MUTAGEN 588
FT /note="S->I: Changes function of the channel including
FT conductance, gating, selectivity and voltage dependence."
FT /evidence="ECO:0000269|PubMed:7744818"
FT MUTAGEN 592
FT /note="S->T: Changes function of the channel including
FT conductance, gating, selectivity and voltage dependence."
FT /evidence="ECO:0000269|PubMed:7744818"
FT CONFLICT 598..599
FT /note="EL -> DV (in Ref. 2; CAA49905)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 698 AA; 78888 MW; B0CF7C15C3CE9763 CRC64;
MLDHTRAPEL NIDLDLHASN SPKGSMKGNQ FKEQDPCPPQ PMQGLGKGDK REEQGLGPEP
SAPRQPTEEE EALIEFHRSY RELFQFFCNN TTIHGAIRLV CSKHNRMKTA FWAVLWLCTF
GMMYWQFALL FEEYLSYPVS LNINLNSDKL VFPAVTVCTL NPYRYTEIKE ELEELDRITE
QTLFDLYKYN SSYTRQAGAR RRSSRDLLGA FPHPLQRLRT PPPPYSGRTA RSGSSSVRDN
NPQVDRKDWK IGFQLCNQNK SDCFYQTYSS GVDAVREWYR FHYINILSRL SDTSPALEEE
ALGNFIFTCR FNQAPCNQAN YSKFHHPMYG NCYTFNDKNN SNLWMSSMPG VNNGLSLTLR
TEQNDFIPLL STVTGARVMV HGQDEPAFMD DGGFNLRPGV ETSISMRKEA LDSLGGNYGD
CTENGSDVPV KNLYPSKYTQ QVCIHSCFQE NMIKKCGCAY IFYPKPKGVE FCDYRKQSSW
GYCYYKLQGA FSLDSLGCFS KCRKPCSVIN YKLSAGYSRW PSVKSQDWIF EMLSLQNNYT
INNKRNGVAK LNIFFKELNY KTNSESPSVT MVSLLSNLGS QWSLWFGSSV LSVVEMAELI
FDLLVITLLM LLRRFRSRYW SPGRGARGAR EVASTPASSF PSRFCPHPTS PPPSLPQQGM
TPPLALTAPP PAYATLGPSA PPLDSAAPDC SACALAAL
