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]
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
urediDužina polipeptidnog lanca je 649 aminokiselina, a molekulska masa 74.270 Da.[5]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MAPGEKIKAK | IKKNLPVTGP | QAPTIKELMR | WYCLNTNTHG | CRRIVVSRGR | ||||
LRRLLWIGFT | LTAVALILWQ | CALLVFSFYT | VSVSIKVHFR | KLDFPAVTIC | ||||
NINPYKYSTV | RHLLADLEQE | TREALKSLYG | FPESRKRREA | ESWNSVSEGK | ||||
QPRFSHRIPL | LIFDQDEKGK | ARDFFTGRKR | KVGGSIIHKA | SNVMHIESKQ | ||||
VVGFQLCSND | TSDCATYTFS | SGINAIQEWY | KLHYMNIMAQ | VPLEKKINMS | ||||
YSAEELLVTC | FFDGVSCDAR | NFTLFHHPMH | GNCYTFNNRE | NETILSTSMG | ||||
GSEYGLQVIL | YINEEEYNPF | LVSSTGAKVI | IHRQDEYPFV | EDVGTEIETA | ||||
MVTSIGMHLT | ESFKLSEPYS | QCTEDGSDVP | IRNIYNAAYS | LQICLHSCFQ | ||||
TKMVEKCGCA | QYSQPLPPAA | NYCNYQQHPN | WMYCYYQLHR | AFVQEELGCQ | ||||
SVCKEACSFK | EWTLTTSLAQ | WPSVVSEKWL | LPVLTWDQGR | QVNKKLNKTD | ||||
LAKLLIFYKD | LNQRSIMESP | ANSIEMLLSN | FGGQLGLWMS | CSVVCVIEII | ||||
EVFFIDFFSI | IARRQWQKAK | EWWAWKQAPP | CPEAPRSPQG | QDNPALDIDD | ||||
DLPTFNSALH | LPPALGTQVP | GTPPPKYNTL | RLERAFSNQL | TDTQMLDEL |
Struktura gena
urediDok 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.
Struktura proteina
urediPrimarne 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
urediOd 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
urediPokazalo se da SCNN1G u interakciji sa:
Također pogledajte
urediReference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000166828 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000000216 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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.
- ^ 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- Staub O, Gautschi I, Ishikawa T, Breitschopf K, Ciechanover A, Schild L, Rotin D (1998). "Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination". EMBO J. 16 (21): 6325–36. doi:10.1093/emboj/16.21.6325. PMC 1170239. PMID 9351815.
- Arai K, Zachman K, Shibasaki T, Chrousos GP (1999). "Polymorphisms of amiloride-sensitive sodium channel subunits in five sporadic cases of pseudohypoaldosteronism: do they have pathologic potential?". J. Clin. Endocrinol. Metab. 84 (7): 2434–7. doi:10.1210/jcem.84.7.5857. PMID 10404817.
- Auerbach SD, Loftus RW, Itani OA, Thomas CP (2000). "Human amiloride-sensitive epithelial Na+ channel gamma subunit promoter: functional analysis and identification of a polypurine-polypyrimidine tract with the potential for triplex DNA formation". Biochem. J. 347 (1): 105–14. doi:10.1042/0264-6021:3470105. PMC 1220937. PMID 10727408.
- Shi H, Asher C, Chigaev A, Yung Y, Reuveny E, Seger R, Garty H (2002). "Interactions of beta and gamma ENaC with Nedd4 can be facilitated by an ERK-mediated phosphorylation". J. Biol. Chem. 277 (16): 13539–47. doi:10.1074/jbc.M111717200. PMID 11805112.
Vanjski linkovi
uredi- SCNN1G protein, human na US National Library of Medicine Medical Subject Headings (MeSH)