Wikipedia

SCNN1G

Gen SCNN1G kod kićmenjaka kodira podjedinicu γ epitelnog natrijevog kanala ENaC . ENaC je sastavljen kao heterotrimer od tri homologne podjedinice α, β i γ ili δ, β i γ. Ostale ENAC podjedinice su kodirane pomoću SCNN1A, SCNN1B i SCNN1D.[5]

SCNN1G
Identifikatori
AliasiSCNN1G
Vanjski ID-jeviOMIM: 600761 MGI: 104695 HomoloGene: 20280 GeneCards: SCNN1G
Lokacija gena (čovjek)
Hromosom 16 (čovjek)
Hrom.Hromosom 16 (čovjek)[1]
Hromosom 16 (čovjek)
Genomska lokacija za SCNN1G
Genomska lokacija za SCNN1G
Bend16p12.2Početak23,182,745 bp[1]
Kraj23,216,883 bp[1]
Lokacija gena (miš)
Hromosom 7 (miš)
Hrom.Hromosom 7 (miš)[2]
Hromosom 7 (miš)
Genomska lokacija za SCNN1G
Genomska lokacija za SCNN1G
Bend7 F2|7 65.07 cMPočetak121,333,702 bp[2]
Kraj121,367,698 bp[2]
Ontologija gena
Molekularna funkcija• sodium channel activity
• ion channel activity
• GO:0001948, GO:0016582 vezivanje za proteine
• WW domain binding
• ligand-gated sodium channel activity
Ćelijska komponenta• integral component of membrane
• membrana
• sodium channel complex
• integral component of plasma membrane
• apical plasma membrane
• Egzosom
• external side of plasma membrane
• nukleoplazma
• ćelijska membrana
Biološki proces• izlučivanje
• sodium ion transmembrane transport
• response to stimulus
• sodium ion transport
• ion transport
• sodium ion homeostasis
• multicellular organismal water homeostasis
• sensory perception of taste
• ion transmembrane transport
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

6340

20278

Ensembl

ENSG00000166828

ENSMUSG00000000216

UniProt

P51170

Q9WU39

RefSeq (mRNK)

NM_001039

NM_011326

RefSeq (bjelančevina)

NP_001030

NP_035456

Lokacija (UCSC)Chr 16: 23.18 – 23.22 MbChr 7: 121.33 – 121.37 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

ENaC se eksprimira u epitelnim ćelijama i razlikuje se od naponski ovisnog natrijwvog kanala koji je uključen u stvaranje akcijskih potencijala u neuronima. Skraćenica za gene koji kodiraju za naponski natrijski kanal počinje sa tri slova: SCN. Za razliku od ovih natrijevih kanala, ENaC je konstitutivno aktivan i ne zavisi od napona. Drugo N u skraćenici (SCNN1) predstavlja da se radi o kanalima koji nisu naponski.

Kod većine kičmenjaka, ioni natrija su glavna determinanta osmolarnosti vanćelijske tečnosti.[6] ENaC omogućava transfer iona natrija, preko epitelne ćelijske membrane u takozvanim "zategnutim epitelima" koji imaju nisku permeabilnost. Protok iona natrija kroz epitel utiče na osmolarnost vanćelijske tečnosti. Dakle, ENaC ima centralnu ulogu u regulaciji homeostaze tjelesnih tekućina i elektrolita i posljedično utiče na krvni pritisak.[7]

Pošto amilorid snažno inhibira ENaC, on se takođe naziva "natrijevim kanalom osetljivim na amilorid".

Aminokiselinska sekvenca uredi

Dužina polipeptidnog lanca je 649 aminokiselina, a molekulska masa 74.270 Da.[5]

1020304050
MAPGEKIKAKIKKNLPVTGPQAPTIKELMRWYCLNTNTHGCRRIVVSRGR
LRRLLWIGFTLTAVALILWQCALLVFSFYTVSVSIKVHFRKLDFPAVTIC
NINPYKYSTVRHLLADLEQETREALKSLYGFPESRKRREAESWNSVSEGK
QPRFSHRIPLLIFDQDEKGKARDFFTGRKRKVGGSIIHKASNVMHIESKQ
VVGFQLCSNDTSDCATYTFSSGINAIQEWYKLHYMNIMAQVPLEKKINMS
YSAEELLVTCFFDGVSCDARNFTLFHHPMHGNCYTFNNRENETILSTSMG
GSEYGLQVILYINEEEYNPFLVSSTGAKVIIHRQDEYPFVEDVGTEIETA
MVTSIGMHLTESFKLSEPYSQCTEDGSDVPIRNIYNAAYSLQICLHSCFQ
TKMVEKCGCAQYSQPLPPAANYCNYQQHPNWMYCYYQLHRAFVQEELGCQ
SVCKEACSFKEWTLTTSLAQWPSVVSEKWLLPVLTWDQGRQVNKKLNKTD
LAKLLIFYKDLNQRSIMESPANSIEMLLSNFGGQLGLWMSCSVVCVIEII
EVFFIDFFSIIARRQWQKAKEWWAWKQAPPCPEAPRSPQGQDNPALDIDD
DLPTFNSALHLPPALGTQVPGTPPPKYNTLRLERAFSNQLTDTQMLDEL

Struktura gena uredi

Dok se ljudski gen SCNN1A nalazi u hromosomskoj sekvenci 12p,[8] ljudski geni koji kodiraju SCNN1B i SCNN1G nalaze se u jukstopoziciji u kratkom kraku hromosoma 16 (16p12-p13). Strukture ljudskih i pacovskih SCNN1G gena prvi su objavili Thomas et al.[9][10] Kasnije studije Saxena et al. prijavile su kompletnu kodirajuću sekvencu ljudskog SCNN1G gena, utvrđujući da ima 13 egzona. Položaji introna su konzervirani u sva tri ljudska ENaC gena, SCNN1A, SCNN1B i SCNN1G.[11] The positions of the introns are also highly conserved across vertebrates See: Ensembl GeneTree.

 
Egzon-intron struktura primarnog transkripta ljudskog SCNN1B. Broj svakog egzona je označen iznad njega. Iznad transkripta je prikazan redni broj transkripta. Klikom na sliku će čitatelj biti upućen na listu transkripata u bazi podataka Ensembl.

Struktura proteina uredi

Primarne strukture sve četiri ENaC podjedinice pokazuju snažnu sličnost. Dakle, ova četiri proteina predstavljaju porodicu proteina koji imaju zajedničkog pretka. U globalnom poravnanju (što znači poravnanje sekvenci duž cele njihove dužine, a ne samo djelimičnog segmenta), ljudska γ podjedinica dijeli 34% identiteta sa β podjedinicom i 27 i 23% identiteta sa α i δ podjedinicama.

Sve četiri sekvence ENaC podjedinica imaju dva hidrofobna dijela koja formiraju dva transmembranska segmenta zvana TM1 i TM2.[12]

Klinički značaj uredi

Od nasljednih poremećaja ovog gene najozbiljniji je Liddleov sindrom. Općenito je uzrokovan mutacijama u PY motivu ili skraćenjem C-terminala, uključujući gubitak PY motiva u β ili γ ENaC podjedinicama.[13][14][15][16][17][18] Iako postoji PY motiv također u α podjedinici, do sada Liddleova bolest nije uočena u vezi s mutacijom u α podjedinici. Liddleov sindrom se nasljeđuje kao autosomno dominantna bolest s fenotipom koji uključuje hipertenziju u ranom nastanku, metaboličku alkalozu i niske razine aktivnosti renina u plazmi i mineralokortikoidnog hormona aldosterona. U nedostatku prepoznatljivog PY motiva, ubikvitin-proteinska ligaza Nedd4-2 ne može se vezati za ENaC podjedinicu i stoga ne može vezati ubikvitin na nju. Posljedično, proteoliza ENaC proteasomom je inhibirana i ENaC se akumulira u membrani što dovodi do pojačane aktivnosti ENaC koja uzrokuje hipertenziju.[19][20][21][22]

Interakcije uredi

Pokazalo se da SCNN1G u interakciji sa:

Također pogledajte uredi

Reference uredi

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000166828 - Ensembl, maj 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000216 - Ensembl, maj 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ a b Hanukoglu I, Hanukoglu A (Jan 2016). "Epithelial sodium channel (ENaC) family: Phylogeny, structure-function, tissue distribution, and associated inherited diseases". Gene. 579 (2): 95–132. doi:10.1016/j.gene.2015.12.061. PMC 4756657. PMID 26772908.
  6. ^ Bourque CW (Jul 2008). "Central mechanisms of osmosensation and systemic osmoregulation". Nature Reviews. Neuroscience. 9 (7): 519–31. doi:10.1038/nrn2400. PMID 18509340. S2CID 205504313.
  7. ^ Rossier BC, Baker ME, Studer RA (Jan 2015). "Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited". Physiological Reviews. 95 (1): 297–340. doi:10.1152/physrev.00011.2014. PMID 25540145.
  8. ^ Ludwig M, Bolkenius U, Wickert L, Marynen P, Bidlingmaier F (May 1998). "Structural organisation of the gene encoding the alpha-subunit of the human amiloride-sensitive epithelial sodium channel". Human Genetics. 102 (5): 576–81. doi:10.1007/s004390050743. PMID 9654208. S2CID 22547152.
  9. ^ Thomas CP, Doggett NA, Fisher R, Stokes JB (Oct 1996). "Genomic organization and the 5' flanking region of the gamma subunit of the human amiloride-sensitive epithelial sodium channel". Journal of Biological Chemistry. 271 (42): 26062–6. doi:10.1074/jbc.271.42.26062. PMID 8824247.
  10. ^ Thomas CP, Auerbach SD, Zhang C, Stokes JB (Mar 1999). "The structure of the rat amiloride-sensitive epithelial sodium channel gamma subunit gene and functional analysis of its promoter". Gene. 228 (1–2): 111–22. doi:10.1016/s0378-1119(99)00016-5. PMID 10072764.
  11. ^ Saxena A, Hanukoglu I, Strautnieks SS, Thompson RJ, Gardiner RM, Hanukoglu A (Nov 1998). "Gene structure of the human amiloride-sensitive epithelial sodium channel beta subunit". Biochemical and Biophysical Research Communications. 252 (1): 208–213. doi:10.1006/bbrc.1998.9625. PMID 9813171.
  12. ^ Canessa CM, Merillat AM, Rossier BC (Dec 1994). "Membrane topology of the epithelial sodium channel in intact cells". The American Journal of Physiology. 267 (6 Pt 1): C1682–90. doi:10.1152/ajpcell.1994.267.6.C1682. PMID 7810611.
  13. ^ Hansson JH, Nelson-Williams C, Suzuki H, Schild L, Shimkets R, Lu Y, Canessa C, Iwasaki T, Rossier B, Lifton RP (1995). "Hypertension caused by a truncated epithelial sodium channel gamma subunit: genetic heterogeneity of Liddle syndrome". Nat. Genet. 11 (1): 76–82. doi:10.1038/ng0995-76. PMID 7550319. S2CID 22106822.
  14. ^ Shimkets RA, Warnock DG, Bositis CM, Nelson-Williams C, Hansson JH, Schambelan M, Gill JR, Ulick S, Milora RV, Findling JW (1994). "Liddle's syndrome: heritable human hypertension caused by mutations in the beta subunit of the epithelial sodium channel". Cell. 79 (3): 407–14. doi:10.1016/0092-8674(94)90250-X. PMID 7954808. S2CID 54282654.
  15. ^ Hansson JH, Schild L, Lu Y, Wilson TA, Gautschi I, Shimkets R, Nelson-Williams C, Rossier BC, Lifton RP (1996). "A de novo missense mutation of the beta subunit of the epithelial sodium channel causes hypertension and Liddle syndrome, identifying a proline-rich segment critical for regulation of channel activity". Proc. Natl. Acad. Sci. U.S.A. 92 (25): 11495–9. doi:10.1073/pnas.92.25.11495. PMC 40428. PMID 8524790.
  16. ^ Inoue J, Iwaoka T, Tokunaga H, Takamune K, Naomi S, Araki M, Takahama K, Yamaguchi K, Tomita K (1998). "A family with Liddle's syndrome caused by a new missense mutation in the beta subunit of the epithelial sodium channel". J. Clin. Endocrinol. Metab. 83 (6): 2210–3. doi:10.1210/jcem.83.6.5030. PMID 9626162.
  17. ^ Persu A, Barbry P, Bassilana F, Houot AM, Mengual R, Lazdunski M, Corvol P, Jeunemaitre X (1998). "Genetic analysis of the beta subunit of the epithelial Na+ channel in essential hypertension". Hypertension. 32 (1): 129–37. doi:10.1161/01.hyp.32.1.129. PMID 9674649.
  18. ^ Uehara Y, Sasaguri M, Kinoshita A, Tsuji E, Kiyose H, Taniguchi H, Noda K, Ideishi M, Inoue J, Tomita K, Arakawa K (1998). "Genetic analysis of the epithelial sodium channel in Liddle's syndrome". J. Hypertens. 16 (8): 1131–5. doi:10.1097/00004872-199816080-00008. PMID 9794716. S2CID 31393115.
  19. ^ Snyder PM, Price MP, McDonald FJ, Adams CM, Volk KA, Zeiher BG, Stokes JB, Welsh MJ (1996). "Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel". Cell. 83 (6): 969–78. doi:10.1016/0092-8674(95)90212-0. PMID 8521520. S2CID 970556.
  20. ^ Tamura H, Schild L, Enomoto N, Matsui N, Marumo F, Rossier BC (1996). "Liddle disease caused by a missense mutation of beta subunit of the epithelial sodium channel gene". J. Clin. Invest. 97 (7): 1780–4. doi:10.1172/JCI118606. PMC 507244. PMID 8601645.
  21. ^ Firsov D, Schild L, Gautschi I, Mérillat AM, Schneeberger E, Rossier BC (1997). "Cell surface expression of the epithelial Na channel and a mutant causing Liddle syndrome: A quantitative approach". Proc. Natl. Acad. Sci. U.S.A. 93 (26): 15370–5. doi:10.1073/pnas.93.26.15370. PMC 26411. PMID 8986818.
  22. ^ Pirozzi G, McConnell SJ, Uveges AJ, Carter JM, Sparks AB, Kay BK, Fowlkes DM (1997). "Identification of novel human WW domain-containing proteins by cloning of ligand targets". J. Biol. Chem. 272 (23): 14611–6. doi:10.1074/jbc.272.23.14611. PMID 9169421.
  23. ^ Farr TJ, Coddington-Lawson SJ, Snyder PM, McDonald FJ (February 2000). "Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits". Biochem. J. 345 (3): 503–9. doi:10.1042/0264-6021:3450503. PMC 1220784. PMID 10642508.
  24. ^ McDonald FJ, Western AH, McNeil JD, Thomas BC, Olson DR, Snyder PM (September 2002). "Ubiquitin-protein ligase WWP2 binds to and downregulates the epithelial Na(+) channel". Am. J. Physiol. Renal Physiol. 283 (3): F431–6. doi:10.1152/ajprenal.00080.2002. PMID 12167593.
  25. ^ Harvey KF, Dinudom A, Cook DI, Kumar S (March 2001). "The Nedd4-like protein KIAA0439 is a potential regulator of the epithelial sodium channel". J. Biol. Chem. 276 (11): 8597–601. doi:10.1074/jbc.C000906200. PMID 11244092.
  26. ^ Berdiev BK, Jovov B, Tucker WC, Naren AP, Fuller CM, Chapman ER, Benos DJ (June 2004). "ENaC subunit-subunit interactions and inhibition by syntaxin 1A". Am. J. Physiol. Renal Physiol. 286 (6): F1100–6. doi:10.1152/ajprenal.00344.2003. PMID 14996668. S2CID 18384316.
  27. ^ Boulkroun S, Ruffieux-Daidié D, Vitagliano JJ, Poirot O, Charles RP, Lagnaz D, Firsov D, Kellenberger S, Staub O (October 2008). "Vasopressin-inducible ubiquitin-specific protease 10 increases ENaC cell surface expression by deubiquitylating and stabilizing sorting nexin 3". Am. J. Physiol. Renal Physiol. 295 (4): F889–900. doi:10.1152/ajprenal.00001.2008. PMID 18632802.
  28. ^ Raikwar NS, Thomas CP (May 2008). "Nedd4-2 isoforms ubiquitinate individual epithelial sodium channel subunits and reduce surface expression and function of the epithelial sodium channel". Am. J. Physiol. Renal Physiol. 294 (5): F1157–65. doi:10.1152/ajprenal.00339.2007. PMC 2424110. PMID 18322022.

Dopunska literatura uredi

Vanjski linkovi uredi


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