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Reviewed, UniProtKB/Swiss-Prot P37088 (SCNNA_HUMAN)

Last modified June 16, 2009. Version 94. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data | Customize display text xml rdf/xml gff fasta
Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents

Names and origin

Protein namesRecommended name:
    Amiloride-sensitive sodium channel subunit alpha
Alternative name(s):
    Epithelial Na(+) channel subunit alpha
    Alpha-ENaC
    SCNEA
    Nonvoltage-gated sodium channel 1 subunit alpha
    Alpha-NaCH
Gene names
Name: SCNN1A
Synonyms: SCNN1
OrganismHomo sapiens (Human)
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length669 AA.
Sequence statusComplete.
Sequence processingThe displayed sequence is not processed.
Protein existenceEvidence at protein level.

General annotation (Comments)

Function

Sodium permeable non-voltage-sensitive ion channel inhibited by the diuretic amiloride. Mediates the electrodiffusion of the luminal sodium (and water, which follows osmotically) through the apical membrane of epithelial cells. Controls the reabsorption of sodium in kidney, colon, lung and sweat glands. Also plays a role in taste perception.

Subunit structure

Heterotetramer of two alpha, one beta and one gamma subunit. A delta subunit can replace the alpha subunit. Interacts with the WW domains of NEDD4, NEDD4L, WWP1 and WWP2. Ref.10 Ref.11 Ref.12 Ref.13

Subcellular location

Apical cell membrane; Multi-pass membrane protein. Note: Apical membrane of epithelial cells.

Tissue specificity

Highly expressed in kidney and lung. Detected at intermediate levels in pancreas and liver, and at low levels in heart and placenta. Isoform 1 and isoform 2 predominate in all tissues. Expression of isoform 3, isoform 4 and isoform 5 is very low or not detectable, except in lung and heart. Ref.9

Induction

By aldosterone. Ref.8

Post-translational modification

Ubiquitinated; this targets individual subunits for endocytosis and proteasome-mediated degradation By similarity.

Involvement in disease

Defects in SCNN1A are a cause of autosomal recessive pseudohypoaldosteronism type 1 (PHA1) [MIM:264350]. PHA1 is a rare salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. There are 2 forms of PHA1: the autosomal recessive form that is severe, and the dominant form which is more milder and due to defects in mineralocorticoid receptor. Autosomal recessive PHA1 is characterized by an often fulminant presentation in the neonatal period with dehydration, hyponatraemia, hyperkalaemia, metabolic acidosis, failure to thrive and weight loss. Ref.15 Ref.17

Sequence similarities

Belongs to the amiloride-sensitive sodium channel family.

Ontologies

Keywords
   Biological processIon transport
Sensory transduction
Sodium transport
Taste
Transport
   Cellular componentCell membrane
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DiseaseDisease mutation
   DomainTransmembrane
   LigandSodium
   Molecular functionIonic channel
Sodium channel
   PTMGlycoprotein
Ubl conjugation
Gene Ontology (GO)
   Biological processexcretion

Traceable author statement. Source: ProtInc

response to stimulus

Inferred from electronic annotation. Source: UniProtKB-KW

sensory perception of taste

Inferred from electronic annotation. Source: UniProtKB-KW

sodium ion transport

Traceable author statement. Source: ProtInc

   Cellular componentapical plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular functionWW domain binding

Inferred from physical interaction. Source: UniProtKB

sodium ion binding

Inferred from electronic annotation. Source: UniProtKB-KW

Complete GO annotation...

Alternative products

This entry describes 5 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: P37088-1)

Also known as: Alpha ENAC1;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: P37088-2)

Also known as: Alpha ENAC2;

The sequence of this isoform differs from the canonical sequence as follows:
     1-1: M → MGMARGSLTRVPGVMGEGTQGPELSLDPDPCSPQSTPGLMKGNKLEEQDPRPLQPIPGLM
Isoform 3 (identifier: P37088-3)

Also known as: Alpha ENACx;

The sequence of this isoform differs from the canonical sequence as follows:
     229-245: CNQNKSDCFYQTYSSGV → ELLSLPPPDVWKLLYFG
     246-669: Missing.
Note: Does not give rise to amiloride-sensitive ion current.
Isoform 4 (identifier: P37088-4)

Also known as: Alpha ENAC-19;

The sequence of this isoform differs from the canonical sequence as follows:
     327-345: Missing.
Note: Amiloride-sensitive ion current is nearly abolished.
Isoform 5 (identifier: P37088-5)

Also known as: Alpha ENAC+22;

The sequence of this isoform differs from the canonical sequence as follows:
     454-454: G → GQVRSLTPVIPALWEAEAGGSRG
Note: Does not give rise to amiloride-sensitive ion current.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 669669Amiloride-sensitive sodium channel subunit alpha
PRO_0000181261

Regions

Topological domain1 – 8585Cytoplasmic Potential
Transmembrane86 – 10621 Potential
Topological domain107 – 562456Extracellular Potential
Transmembrane563 – 58321 Potential
Topological domain584 – 66986Cytoplasmic Potential

Amino acid modifications

Glycosylation2321N-linked (GlcNAc...) Potential
Glycosylation2931N-linked (GlcNAc...) Potential
Glycosylation3121N-linked (GlcNAc...) Potential
Glycosylation3971N-linked (GlcNAc...) Potential
Glycosylation5111N-linked (GlcNAc...) Potential

Natural variations

Alternative sequence11M → MGMARGSLTRVPGVMGEGTQ GPELSLDPDPCSPQSTPGLM KGNKLEEQDPRPLQPIPGLM in isoform 2.
VSP_007719
Alternative sequence229 – 24517CNQNK…YSSGV → ELLSLPPPDVWKLLYFG in isoform 3.
VSP_007720
Alternative sequence246 – 669424Missing in isoform 3.
VSP_007721
Alternative sequence327 – 34519Missing in isoform 4.
VSP_007722
Alternative sequence4541G → GQVRSLTPVIPALWEAEAGG SRG in isoform 5.
VSP_007723
Natural variant3271G → C in PHA1. Ref.17
VAR_026518
Natural variant4021P → H: dbSNP rs13306616.
VAR_052035
Natural variant4931W → R Rare polymorphism. dbSNP rs5742912. Ref.15
VAR_015833
Natural variant5621S → L in PHA1. Ref.15
VAR_015834
Natural variant6181C → F: dbSNP rs3741913.
VAR_022142
Natural variant6631T → A: dbSNP rs2228576. Ref.6 Ref.14 Ref.16
VAR_015835

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 (Alpha ENAC1) [UniParc].

Last modified October 1, 1994. Version 1.
Checksum: 2CCF342E7DF32E72

FASTA66975,704
        10         20         30         40         50         60 
MEGNKLEEQD SSPPQSTPGL MKGNKREEQG LGPEPAAPQQ PTAEEEALIE FHRSYRELFE 

        70         80         90        100        110        120 
FFCNNTTIHG AIRLVCSQHN RMKTAFWAVL WLCTFGMMYW QFGLLFGEYF SYPVSLNINL 

       130        140        150        160        170        180 
NSDKLVFPAV TICTLNPYRY PEIKEELEEL DRITEQTLFD LYKYSSFTTL VAGSRSRRDL 

       190        200        210        220        230        240 
RGTLPHPLQR LRVPPPPHGA RRARSVASSL RDNNPQVDWK DWKIGFQLCN QNKSDCFYQT 

       250        260        270        280        290        300 
YSSGVDAVRE WYRFHYINIL SRLPETLPSL EEDTLGNFIF ACRFNQVSCN QANYSHFHHP 

       310        320        330        340        350        360 
MYGNCYTFND KNNSNLWMSS MPGINNGLSL MLRAEQNDFI PLLSTVTGAR VMVHGQDEPA 

       370        380        390        400        410        420 
FMDDGGFNLR PGVETSISMR KETLDRLGGD YGDCTKNGSD VPVENLYPSK YTQQVCIHSC 

       430        440        450        460        470        480 
FQESMIKECG CAYIFYPRPQ NVEYCDYRKH SSWGYCYYKL QVDFSSDHLG CFTKCRKPCS 

       490        500        510        520        530        540 
VTSYQLSAGY SRWPSVTSQE WVFQMLSRQN NYTVNNKRNG VAKVNIFFKE LNYKTNSESP 

       550        560        570        580        590        600 
SVTMVTLLSN LGSQWSLWFG SSVLSVVEMA ELVFDLLVIM FLMLLRRFRS RYWSPGRGGR 

       610        620        630        640        650        660 
GAQEVASTLA SSPPSHFCPH PMSLSLSQPG PAPSPALTAP PPAYATLGPR PSPGGSAGAS 


SSTCPLGGP 

« Hide

Isoform 2 (Alpha ENAC2).

Checksum: 206613374DFB1800
Show »

FASTA72881,856
Isoform 3 (Alpha ENACx).

Checksum: FFDC0622FFA37329
Show »

FASTA24528,328
Isoform 4 (Alpha ENAC-19).

Checksum: 5866D42CCAF6F8B4
Show »

FASTA65073,603
Isoform 5 (Alpha ENAC+22).

Checksum: 07B981FBE74AE30B
Show »

FASTA69177,980

References

« Hide 'large scale' references
[1]"The lung amiloride-sensitive Na+ channel: biophysical properties, pharmacology, ontogenesis, and molecular cloning."
Voilley N., Lingueglia E., Champigny G., Mattei M.-G., Waldmann R., Lazdunski M., Barbry P.
Proc. Natl. Acad. Sci. U.S.A. 91:247-251(1994) [PubMed: 8278374] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
Tissue: Lung.
[2]"Cloning, expression, and tissue distribution of a human amiloride-sensitive Na+ channel."
McDonald F.J., Snyder P.M., McCray P.B. Jr., Welsh M.J.
Am. J. Physiol. 266:L728-L734(1994) [PubMed: 8023962] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
Tissue: Kidney.
[3]"Structural organisation of the gene encoding the alpha-subunit of the human amiloride-sensitive epithelial sodium channel."
Ludwig M., Bolkenius U., Wickert L., Marynen P., Bidlingmaier F.
Hum. Genet. 102:576-581(1998) [PubMed: 9654208] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[4]"Hormonal regulation and genomic organization of the human amiloride-sensitive epithelial sodium channel alpha subunit gene."
Chow Y.H., Wang Y., Plumb J., O'Brodovich H., Hu J.
Pediatr. Res. 46:208-214(1999) [PubMed: 10447117] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA].
[5]"Upregulated expression of ENaC in human CF nasal epithelium."
Bangel N., Dahlhoff C., Sobczak K., Weber W.M., Kusche-Vihrog K.
J. Cyst. Fibros. 7:197-205(2008) [PubMed: 17766193] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT ALA-663.
Tissue: Nasal epithelium.
[6]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT ALA-663.
Tissue: Colon and Lung.
[7]"5' heterogeneity in epithelial sodium channel alpha-subunit mRNA leads to distinct NH2-terminal variant proteins."
Thomas C.P., Auerbach S.D., Stokes J.B., Volk K.A.
Am. J. Physiol. 274:C1312-C1323(1998) [PubMed: 9612219] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50, ALTERNATIVE SPLICING (ISOFORMS 1 AND 2).
Tissue: Kidney.
[8]"The alpha-subunit of the epithelial sodium channel is an aldosterone-induced transcript in mammalian collecting ducts, and this transcriptional response is mediated via distinct cis-elements in the 5'-flanking region of the gene."
Mick V.E., Itani O.A., Loftus R.W., Husted R.F., Schmidt T.J., Thomas C.P.
Mol. Endocrinol. 15:575-588(2001) [PubMed: 11266509] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-50 (ISOFORMS 1 AND 2), INDUCTION.
Tissue: Placenta.
[9]"Cloning and functional studies of splice variants of the alpha-subunit of the amiloride-sensitive Na+ channel."
Tucker J.K., Tamba K., Lee Y.-J., Shen L.-L., Warnock D.G., Oh Y.
Am. J. Physiol. 274:C1081-C1089(1998) [PubMed: 9575806] [Abstract]
Cited for: ALTERNATIVE SPLICING (ISOFORMS 1; 3; 4 AND 5), TISSUE SPECIFICITY.
[10]"Identification of novel human WW domain-containing proteins by cloning of ligand targets."
Pirozzi G., McConnell S.J., Uveges A.J., Carter J.M., Sparks A.B., Kay B.K., Fowlkes D.M.
J. Biol. Chem. 272:14611-14616(1997) [PubMed: 9169421] [Abstract]
Cited for: INTERACTION WITH WWP1 AND WWP2.
[11]"The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel."
Harvey K.F., Dinudom A., Cook D.I., Kumar S.
J. Biol. Chem. 276:8597-8601(2001) [PubMed: 11244092] [Abstract]
Cited for: INTERACTION WITH NEDD4 AND NEDD4L.
[12]"Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel."
McDonald F.J., Western A.H., McNeil J.D., Thomas B.C., Olson D.R., Snyder P.M.
Am. J. Physiol. 283:F431-F436(2002) [PubMed: 12167593] [Abstract]
Cited for: INTERACTION WITH NEDD4 AND WWP2.
[13]"Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel."
Snyder P.M., Olson D.R., Thomas B.C.
J. Biol. Chem. 277:5-8(2002) [PubMed: 11696533] [Abstract]
Cited for: INTERACTION WITH NEDD4 AND NEDD4L.
[14]"Polymorphisms of amiloride-sensitive sodium channel subunits in five sporadic cases of pseudohypoaldosteronism: do they have pathologic potential?"
Arai K., Zachman K., Shibasaki T., Chrousos G.P.
J. Clin. Endocrinol. Metab. 84:2434-2437(1999) [PubMed: 10404817] [Abstract]
Cited for: VARIANT ALA-663.
[15]"Lung symptoms in pseudohypoaldosteronism type 1 are associated with deficiency of the alpha-subunit of the epithelial sodium channel."
Schaedel C., Marthinsen L., Kristoffersson A.-C., Kornfalt R., Nilsson K.O., Orlenius B., Holmberg L.
J. Pediatr. 135:739-745(1999) [PubMed: 10586178] [Abstract]
Cited for: VARIANT PHA1 LEU-562, VARIANT ARG-493.
[16]"Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-, beta-, and gamma-subunit genes."
Saxena A., Hanukoglu I., Saxena D., Thompson R.J., Gardiner R.M., Hanukoglu A.
J. Clin. Endocrinol. Metab. 87:3344-3350(2002) [PubMed: 12107247] [Abstract]
Cited for: VARIANT ALA-663.
[17]"Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism."
Edelheit O., Hanukoglu I., Gizewska M., Kandemir N., Tenenbaum-Rakover Y., Yurdakoek M., Zajaczek S., Hanukoglu A.
Clin. Endocrinol. (Oxf.) 62:547-553(2005) [PubMed: 15853823] [Abstract]
Cited for: VARIANT PHA1 CYS-327.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

X76180 mRNA. Translation: CAA53773.1.
L29007 Genomic DNA. Translation: AAA21813.1.
Z92978 expand/collapse EMBL AC list , Z92979, Z92980, Z92981 Genomic DNA. Translation: CAB07505.1.
AF060913 expand/collapse EMBL AC list , AF060910, AF060911, AF060912 Genomic DNA. Translation: AAD28355.1.
DQ402522 mRNA. Translation: ABD72218.1.
BC006526 mRNA. Translation: AAH06526.2. Different initiation.
BC062613 mRNA. Translation: AAH62613.1.
U81961 Genomic DNA. Translation: AAC31773.1.
U81961 Genomic DNA. Translation: AAC31774.1.
IPIIPI00019931.
IPI00334114.
IPI00334115.
IPI00334116.
IPI00334117.
PIRA49585.
RefSeqNP_001029.1.
UniGeneHs.279594
Hs.591047

3D structure databases

ModBaseSearch...

Protein family/group databases

TCDB1.A.6.1.1. epithelial Na+ channel (ENaC) family.

PTM databases

PhosphoSiteP37088.

Proteomic databases

PRIDEP37088.

Genome annotation databases

EnsemblENSG00000111319. Homo sapiens. [Contig view]
GeneID6337.
KEGGhsa:6337.

Organism-specific databases

GeneCardsGC12M006326.
H-InvDBHIX0010361.
HGNCHGNC:10599. SCNN1A.
HPAHPA012743.
HPA012939.
MIM264350. phenotype.
600228. gene.
Orphanet171876. Generalized pseudohypoaldosteronism type I.
756. Pseudohypoaldosteronism, type 1.
PharmGKBPA305.
GenAtlasSearch...

Phylogenomic databases

HOVERGENP37088.
OMAP37088. CNQANYS.

Gene expression databases

ArrayExpressP37088.
BgeeP37088.
CleanExHS_SCNN1A.
GermOnlineENSG00000111319. Homo sapiens.

Family and domain databases

InterProIPR004724. EnaC.
IPR001873. Na+channel_ASC.
[Graphical view]
PANTHERPTHR11690. Na+channel_ASC. 1 hit.
PfamPF00858. ASC. 1 hit.
[Graphical view]
PRINTSPR01078. AMINACHANNEL.
TIGRFAMsTIGR00859. ENaC. 1 hit.
PROSITEPS01206. ASC. 1 hit.
[Graphical view]
ProtoNetSearch...

Other Resources

DrugBankDB00594. Amiloride.
DB00384. Triamterene.
NextBio24608.
SOURCESearch...

Entry information

Entry nameSCNNA_HUMAN
AccessionPrimary (citable) accession number: P37088
Secondary accession number(s): A5X2U9 expand/collapse secondary AC list , O43271, Q6GSQ6, Q9UM64
Entry history
Integrated into UniProtKB/Swiss-Prot: October 1, 1994
Last sequence update: October 1, 1994
Last modified: June 16, 2009
This is version 94 of the entry and version 1 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation projectHPI (Human Proteome Initiative)

Relevant documents

Human chromosome 12

Human chromosome 12: entries, gene names and cross-references to MIM

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

SIMILARITY comments

Index of protein domains and families

Names and origin · Protein attributes · General annotation (Comments) · Ontologies · Alternative products · Sequence annotation (Features) · Sequences · References · Web resources · Cross-references · Entry information · Relevant documents