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1.A.6.1.1
Epithelial Na+ channel, ENaC (regulates salt and fluid homeostasis and blood pressure; regulated by Nedd4 isoforms and SGK1, 2 and 3 kinases) (Henry et al., 2003; Pao 2012).  Cd2+ inhibits α-ENaC by binding to the internal pore where it interacts with residues in TMS2 (Takeda et al., 2007).  The channel is regulated by palmitoylation of the beta subunit which modulates gating (Mueller et al. 2010). ENaCs are more selective for Naa+ over other cations than ASICs (Yang and Palmer 2018). ENaC plays a role in chronic obstructive pulmonary diseases (COPD) (Zhao et al. 2014). The hetrodimeric complex can consist of αβγ or δβγ subunits, depending on the tissue (Giraldez et al. 2012).  The α- and γ-subunits of the epithelial Na+ channel interact directly with the Na+:Cl- cotransporter, NCC, in the renal distal tubule with functional cosequences, and together they determine bodily salt balance and blood pressure (Mistry et al. 2016).  ENaC is regulated by syntaxins (Saxena et al. 2006). The cryoEM structure has been solved (Noreng et al. 2018). Interactions between the epithelial sodium channel gamma-subunit and claudin-8 modulates paracellular sodium permeability in the renal collecting duct (Sassi et al. 2020).

Accession Number:P37088
Protein Name:SCAA aka SCNN1 aka SCNN1A
Length:669
Molecular Weight:75704.00
Species:Homo sapiens (Human) [9606]
Number of TMSs:2
Location1 / Topology2 / Orientation3: Apical cell membrane1 / Multi-pass membrane protein2
Substrate Na+

Cross database links:

Genevestigator: P37088
eggNOG: prNOG19108
RefSeq: NP_001029.1    NP_001153047.1    NP_001153048.1   
Entrez Gene ID: 6337   
Pfam: PF00858   
Drugbank: Drugbank Link   
OMIM: 264350  phenotype
600228  gene
613021  phenotype
KEGG: hsa:6337   

Gene Ontology

GO:0016324 C:apical plasma membrane
GO:0050699 F:WW domain binding
GO:0007588 P:excretion
GO:0050896 P:response to stimulus
GO:0050909 P:sensory perception of taste
GO:0006814 P:sodium ion transport

References (21)

[1] “The lung amiloride-sensitive Na+ channel: biophysical properties, pharmacology, ontogenesis, and molecular cloning.”  Voilley N.et.al.   8278374
[2] “Cloning, expression, and tissue distribution of a human amiloride-sensitive Na+ channel.”  McDonald F.J.et.al.   8023962
[3] “Structural organisation of the gene encoding the alpha-subunit of the human amiloride-sensitive epithelial sodium channel.”  Ludwig M.et.al.   9654208
[4] “Hormonal regulation and genomic organization of the human amiloride-sensitive epithelial sodium channel alpha subunit gene.”  Chow Y.H.et.al.   10447117
[5] “Upregulated expression of ENaC in human CF nasal epithelium.”  Bangel N.et.al.   17766193
[6] “The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).”  The MGC Project Teamet.al.   15489334
[7] “5' heterogeneity in epithelial sodium channel alpha-subunit mRNA leads to distinct NH2-terminal variant proteins.”  Thomas C.P.et.al.   9612219
[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.et.al.   11266509
[9] “Cloning and functional studies of splice variants of the alpha-subunit of the amiloride-sensitive Na+ channel.”  Tucker J.K.et.al.   9575806
[10] “Identification of novel human WW domain-containing proteins by cloning of ligand targets.”  Pirozzi G.et.al.   9169421
[11] “The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel.”  Harvey K.F.et.al.   11244092
[12] “Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel.”  McDonald F.J.et.al.   12167593
[13] “Genetic variants in the epithelial sodium channel in relation to aldosterone and potassium excretion and risk for hypertension.”  Ambrosius W.T.et.al.   10523338
[14] “Serum and glucocorticoid-regulated kinase modulates Nedd4-2-mediated inhibition of the epithelial Na+ channel.”  Snyder P.M.et.al.   11696533
[15] “Polymorphisms of amiloride-sensitive sodium channel subunits in five sporadic cases of pseudohypoaldosteronism: do they have pathologic potential?”  Arai K.et.al.   10404817
[16] “Lung symptoms in pseudohypoaldosteronism type 1 are associated with deficiency of the alpha-subunit of the epithelial sodium channel.”  Schaedel C.et.al.   10586178
[17] “Novel mutations responsible for autosomal recessive multisystem pseudohypoaldosteronism and sequence variants in epithelial sodium channel alpha-, beta-, and gamma-subunit genes.”  Saxena A.et.al.   12107247
[18] “Impact of alphaENaC polymorphisms on the risk of ischemic cerebrovascular events: a multicenter case-control study.”  Hsieh K.et.al.   15734793
[19] “Novel mutations in epithelial sodium channel (ENaC) subunit genes and phenotypic expression of multisystem pseudohypoaldosteronism.”  Edelheit O.et.al.   15853823
[20] “Mutations in the beta-subunit of the epithelial Na+ channel in patients with a cystic fibrosis-like syndrome.”  Sheridan M.B.et.al.   16207733
[21] “Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease.”  Azad A.K.et.al.   19462466
Structure:
2M3O   6BQN   6WTH     

External Searches:

  • Search: DB with
  • BLAST ExPASy (Swiss Institute of Bioinformatics (SIB) BLAST)
  • CDD Search (Conserved Domain Database)
  • Search COGs (Clusters of Orthologous Groups of proteins)
  • 2° Structure (Network Protein Sequence Analysis)

Analyze:

Predict TMSs (Predict number of transmembrane segments)
Window Size: Angle:  
FASTA formatted sequence
1:	MEGNKLEEQD SSPPQSTPGL MKGNKREEQG LGPEPAAPQQ PTAEEEALIE FHRSYRELFE 
61:	FFCNNTTIHG AIRLVCSQHN RMKTAFWAVL WLCTFGMMYW QFGLLFGEYF SYPVSLNINL 
121:	NSDKLVFPAV TICTLNPYRY PEIKEELEEL DRITEQTLFD LYKYSSFTTL VAGSRSRRDL 
181:	RGTLPHPLQR LRVPPPPHGA RRARSVASSL RDNNPQVDWK DWKIGFQLCN QNKSDCFYQT 
241:	YSSGVDAVRE WYRFHYINIL SRLPETLPSL EEDTLGNFIF ACRFNQVSCN QANYSHFHHP 
301:	MYGNCYTFND KNNSNLWMSS MPGINNGLSL MLRAEQNDFI PLLSTVTGAR VMVHGQDEPA 
361:	FMDDGGFNLR PGVETSISMR KETLDRLGGD YGDCTKNGSD VPVENLYPSK YTQQVCIHSC 
421:	FQESMIKECG CAYIFYPRPQ NVEYCDYRKH SSWGYCYYKL QVDFSSDHLG CFTKCRKPCS 
481:	VTSYQLSAGY SRWPSVTSQE WVFQMLSRQN NYTVNNKRNG VAKVNIFFKE LNYKTNSESP 
541:	SVTMVTLLSN LGSQWSLWFG SSVLSVVEMA ELVFDLLVIM FLMLLRRFRS RYWSPGRGGR 
601:	GAQEVASTLA SSPPSHFCPH PMSLSLSQPG PAPSPALTAP PPAYATLGPR PSPGGSAGAS 
661:	SSTCPLGGP