The transport of iron between cells is mediated by transferrin. However, iron can also enter and leave cells not only by itself, but also in the form of heme and siderophores. When entering the cell via the main path (by transferrin endocytosis), its goal is not the (still elusive) chelated iron pool in the cytosol nor the lysosomes but the mitochondria, where heme is synthesized and iron-sulfur clusters are assembled (Kurz et al,2008, Hower et al 2009, Richardson et al 2010).Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=917937
Comments
HomologyConvert
This pathway was inferred from Homo sapiens pathway WP2670(76854) with a 88.0% conversion rate.
Nozu K, Inagaki T, Fu XJ, Nozu Y, Kaito H, Kanda K, Sekine T, Igarashi T, Nakanishi K, Yoshikawa N, Iijima K, Matsuo M.; ''Molecular analysis of digenic inheritance in Bartter syndrome with sensorineural deafness.''; PubMedEurope PMCScholia
Paulusma CC, Oude Elferink RP.; ''The type 4 subfamily of P-type ATPases, putative aminophospholipid translocases with a role in human disease.''; PubMedEurope PMCScholia
Vulpe C, Levinson B, Whitney S, Packman S, Gitschier J.; ''Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase.''; PubMedEurope PMCScholia
Cutting GR, Lu L, O'Hara BF, Kasch LM, Montrose-Rafizadeh C, Donovan DM, Shimada S, Antonarakis SE, Guggino WB, Uhl GR.; ''Cloning of the gamma-aminobutyric acid (GABA) rho 1 cDNA: a GABA receptor subunit highly expressed in the retina.''; PubMedEurope PMCScholia
Tunwell RE, Wickenden C, Bertrand BM, Shevchenko VI, Walsh MB, Allen PD, Lai FA.; ''The human cardiac muscle ryanodine receptor-calcium release channel: identification, primary structure and topological analysis.''; PubMedEurope PMCScholia
Kurz T, Terman A, Gustafsson B, Brunk UT.; ''Lysosomes in iron metabolism, ageing and apoptosis.''; PubMedEurope PMCScholia
Hadingham KL, Wafford KA, Thompson SA, Palmer KJ, Whiting PJ.; ''Expression and pharmacology of human GABAA receptors containing gamma 3 subunits.''; PubMedEurope PMCScholia
Yang XL, Miura N, Kawarada Y, Terada K, Petrukhin K, Gilliam T, Sugiyama T.; ''Two forms of Wilson disease protein produced by alternative splicing are localized in distinct cellular compartments.''; PubMedEurope PMCScholia
Waldegger S, Jentsch TJ.; ''Functional and structural analysis of ClC-K chloride channels involved in renal disease.''; PubMedEurope PMCScholia
Choudhury K, McQuillin A, Puri V, Pimm J, Datta S, Thirumalai S, Krasucki R, Lawrence J, Bass NJ, Quested D, Crombie C, Fraser G, Walker N, Nadeem H, Johnson S, Curtis D, St Clair D, Gurling HM.; ''A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia.''; PubMedEurope PMCScholia
Tian Y, Schreiber R, Kunzelmann K.; ''Anoctamins are a family of Ca2+-activated Cl- channels.''; PubMedEurope PMCScholia
Stobrawa SM, Breiderhoff T, Takamori S, Engel D, Schweizer M, Zdebik AA, Bösl MR, Ruether K, Jahn H, Draguhn A, Jahn R, Jentsch TJ.; ''Disruption of ClC-3, a chloride channel expressed on synaptic vesicles, leads to a loss of the hippocampus.''; PubMedEurope PMCScholia
Edenberg HJ, Dick DM, Xuei X, Tian H, Almasy L, Bauer LO, Crowe RR, Goate A, Hesselbrock V, Jones K, Kwon J, Li TK, Nurnberger JI Jr, O'Connor SJ, Reich T, Rice J, Schuckit MA, Porjesz B, Foroud T, Begleiter H.; ''Variations in GABRA2, encoding the alpha 2 subunit of the GABA(A) receptor, are associated with alcohol dependence and with brain oscillations.''; PubMedEurope PMCScholia
Khan ZU, Fernando LP, Escribá P, Busquets X, Mallet J, Miralles CP, Filla M, De Blas AL.; ''Antibodies to the human gamma 2 subunit of the gamma-aminobutyric acidA/benzodiazepine receptor.''; PubMedEurope PMCScholia
Koch MC, Steinmeyer K, Lorenz C, Ricker K, Wolf F, Otto M, Zoll B, Lehmann-Horn F, Grzeschik KH, Jentsch TJ.; ''The skeletal muscle chloride channel in dominant and recessive human myotonia.''; PubMedEurope PMCScholia
Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, Kirkness EF.; ''The 5-HT3B subunit is a major determinant of serotonin-receptor function.''; PubMedEurope PMCScholia
Ruiz A, Bhat SP, Bok D.; ''Expression and synthesis of the Na,K-ATPase beta 2 subunit in human retinal pigment epithelium.''; PubMedEurope PMCScholia
Chen H, Attieh ZK, Dang T, Huang G, van der Hee RM, Vulpe C.; ''Decreased hephaestin expression and activity leads to decreased iron efflux from differentiated Caco2 cells.''; PubMedEurope PMCScholia
Zorzato F, Fujii J, Otsu K, Phillips M, Green NM, Lai FA, Meissner G, MacLennan DH.; ''Molecular cloning of cDNA encoding human and rabbit forms of the Ca2+ release channel (ryanodine receptor) of skeletal muscle sarcoplasmic reticulum.''; PubMedEurope PMCScholia
Maeda M, Oshiman K, Tamura S, Futai M.; ''Human gastric (H+ + K+)-ATPase gene. Similarity to (Na+ + K+)-ATPase genes in exon/intron organization but difference in control region.''; PubMedEurope PMCScholia
Borsani G, Rugarli EI, Taglialatela M, Wong C, Ballabio A.; ''Characterization of a human and murine gene (CLCN3) sharing similarities to voltage-gated chloride channels and to a yeast integral membrane protein.''; PubMedEurope PMCScholia
Lu B, Zhang Q, Wang H, Wang Y, Nakayama M, Ren D.; ''Extracellular calcium controls background current and neuronal excitability via an UNC79-UNC80-NALCN cation channel complex.''; PubMedEurope PMCScholia
Farr TJ, Coddington-Lawson SJ, Snyder PM, McDonald FJ.; ''Human Nedd4 interacts with the human epithelial Na+ channel: WW3 but not WW1 binds to Na+-channel subunits.''; PubMedEurope PMCScholia
Sun H, Tsunenari T, Yau KW, Nathans J.; ''The vitelliform macular dystrophy protein defines a new family of chloride channels.''; PubMedEurope PMCScholia
Zdebik AA, Zifarelli G, Bergsdorf EY, Soliani P, Scheel O, Jentsch TJ, Pusch M.; ''Determinants of anion-proton coupling in mammalian endosomal CLC proteins.''; PubMedEurope PMCScholia
Niemeyer MI, Cid LP, Yusef YR, Briones R, Sepúlveda FV.; ''Voltage-dependent and -independent titration of specific residues accounts for complex gating of a ClC chloride channel by extracellular protons.''; PubMedEurope PMCScholia
Staub O, Abriel H, Plant P, Ishikawa T, Kanelis V, Saleki R, Horisberger JD, Schild L, Rotin D.; ''Regulation of the epithelial Na+ channel by Nedd4 and ubiquitination.''; PubMedEurope PMCScholia
Griffiths TA, Mauk AG, MacGillivray RT.; ''Recombinant expression and functional characterization of human hephaestin: a multicopper oxidase with ferroxidase activity.''; PubMedEurope PMCScholia
Lu B, Su Y, Das S, Liu J, Xia J, Ren D.; ''The neuronal channel NALCN contributes resting sodium permeability and is required for normal respiratory rhythm.''; PubMedEurope PMCScholia
Pangrazio A, Pusch M, Caldana E, Frattini A, Lanino E, Tamhankar PM, Phadke S, Lopez AG, Orchard P, Mihci E, Abinun M, Wright M, Vettenranta K, Bariae I, Melis D, Tezcan I, Baumann C, Locatelli F, Zecca M, Horwitz E, Mansour LS, Van Roij M, Vezzoni P, Villa A, Sobacchi C.; ''Molecular and clinical heterogeneity in CLCN7-dependent osteopetrosis: report of 20 novel mutations.''; PubMedEurope PMCScholia
Grenningloh G, Schmieden V, Schofield PR, Seeburg PH, Siddique T, Mohandas TK, Becker CM, Betz H.; ''Alpha subunit variants of the human glycine receptor: primary structures, functional expression and chromosomal localization of the corresponding genes.''; PubMedEurope PMCScholia
Taglicht D, Padan E, Schuldiner S.; ''Proton-sodium stoichiometry of NhaA, an electrogenic antiporter from Escherichia coli.''; PubMedEurope PMCScholia
Soundararajan R, Melters D, Shih IC, Wang J, Pearce D.; ''Epithelial sodium channel regulated by differential composition of a signaling complex.''; PubMedEurope PMCScholia
Yang YD, Cho H, Koo JY, Tak MH, Cho Y, Shim WS, Park SP, Lee J, Lee B, Kim BM, Raouf R, Shin YK, Oh U.; ''TMEM16A confers receptor-activated calcium-dependent chloride conductance.''; PubMedEurope PMCScholia
Kawasaki M, Fukuma T, Yamauchi K, Sakamoto H, Marumo F, Sasaki S.; ''Identification of an acid-activated Cl(-) channel from human skeletal muscles.''; PubMedEurope PMCScholia
Takeuchi Y, Uchida S, Marumo F, Sasaki S.; ''Cloning, tissue distribution, and intrarenal localization of ClC chloride channels in human kidney.''; PubMedEurope PMCScholia
Voilley N, de Weille J, Mamet J, Lazdunski M.; ''Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors.''; PubMedEurope PMCScholia
Xiang M, Feng M, Muend S, Rao R.; ''A human Na+/H+ antiporter sharing evolutionary origins with bacterial NhaA may be a candidate gene for essential hypertension.''; PubMedEurope PMCScholia
Spamer C, Heilmann C, Gerok W.; ''Ca2+-activated ATPase in microsomes from human liver.''; PubMedEurope PMCScholia
West AP Jr, Giannetti AM, Herr AB, Bennett MJ, Nangiana JS, Pierce JR, Weiner LP, Snow PM, Bjorkman PJ.; ''Mutational analysis of the transferrin receptor reveals overlapping HFE and transferrin binding sites.''; PubMedEurope PMCScholia
Bokkala S, el-Daher SS, Kakkar VV, Wuytack F, Authi KS.; ''Localization and identification of Ca2+ATPases in highly purified human platelet plasma and intracellular membranes. Evidence that the monoclonal antibody PL/IM 430 recognizes the SERCA 3 Ca2+ATPase in human platelets.''; PubMedEurope PMCScholia
Harrison PM, Arosio P.; ''The ferritins: molecular properties, iron storage function and cellular regulation.''; PubMedEurope PMCScholia
Scudieri P, Sondo E, Ferrera L, Galietta LJ.; ''The anoctamin family: TMEM16A and TMEM16B as calcium-activated chloride channels.''; PubMedEurope PMCScholia
Petrukhin K, Koisti MJ, Bakall B, Li W, Xie G, Marknell T, Sandgren O, Forsman K, Holmgren G, Andreasson S, Vujic M, Bergen AA, McGarty-Dugan V, Figueroa D, Austin CP, Metzker ML, Caskey CT, Wadelius C.; ''Identification of the gene responsible for Best macular dystrophy.''; PubMedEurope PMCScholia
Graves AR, Curran PK, Smith CL, Mindell JA.; ''The Cl-/H+ antiporter ClC-7 is the primary chloride permeation pathway in lysosomes.''; PubMedEurope PMCScholia
Brailoiu E, Churamani D, Cai X, Schrlau MG, Brailoiu GC, Gao X, Hooper R, Boulware MJ, Dun NJ, Marchant JS, Patel S.; ''Essential requirement for two-pore channel 1 in NAADP-mediated calcium signaling.''; PubMedEurope PMCScholia
Hower V, Mendes P, Torti FM, Laubenbacher R, Akman S, Shulaev V, Torti SV.; ''A general map of iron metabolism and tissue-specific subnetworks.''; PubMedEurope PMCScholia
Ishibashi K, Marumo F.; ''Molecular cloning of a DEG/ENaC sodium channel cDNA from human testis.''; PubMedEurope PMCScholia
Zhang W, Mojsilovic-Petrovic J, Andrade MF, Zhang H, Ball M, Stanimirovic DB.; ''The expression and functional characterization of ABCG2 in brain endothelial cells and vessels.''; PubMedEurope PMCScholia
Jutabha P, Anzai N, Kitamura K, Taniguchi A, Kaneko S, Yan K, Yamada H, Shimada H, Kimura T, Katada T, Fukutomi T, Tomita K, Urano W, Yamanaka H, Seki G, Fujita T, Moriyama Y, Yamada A, Uchida S, Wempe MF, Endou H, Sakurai H.; ''Human sodium phosphate transporter 4 (hNPT4/SLC17A3) as a common renal secretory pathway for drugs and urate.''; PubMedEurope PMCScholia
Pangrazio A, Poliani PL, Megarbane A, Lefranc G, Lanino E, Di Rocco M, Rucci F, Lucchini F, Ravanini M, Facchetti F, Abinun M, Vezzoni P, Villa A, Frattini A.; ''Mutations in OSTM1 (grey lethal) define a particularly severe form of autosomal recessive osteopetrosis with neural involvement.''; PubMedEurope PMCScholia
Fujii J, Willard HF, MacLennan DH.; ''Characterization and localization to human chromosome 1 of human fast-twitch skeletal muscle calsequestrin gene.''; PubMedEurope PMCScholia
Verma AK, Filoteo AG, Stanford DR, Wieben ED, Penniston JT, Strehler EE, Fischer R, Heim R, Vogel G, Mathews S.; ''Complete primary structure of a human plasma membrane Ca2+ pump.''; PubMedEurope PMCScholia
Handford CA, Lynch JW, Baker E, Webb GC, Ford JH, Sutherland GR, Schofield PR.; ''The human glycine receptor beta subunit: primary structure, functional characterisation and chromosomal localisation of the human and murine genes.''; PubMedEurope PMCScholia
Steinmeyer K, Lorenz C, Pusch M, Koch MC, Jentsch TJ.; ''Multimeric structure of ClC-1 chloride channel revealed by mutations in dominant myotonia congenita (Thomsen).''; PubMedEurope PMCScholia
Taske NL, Eyre HJ, O'Brien RO, Sutherland GR, Denborough MA, Foster PS.; ''Molecular cloning of the cDNA encoding human skeletal muscle triadin and its localisation to chromosome 6q22-6q23.''; PubMedEurope PMCScholia
Fischer M, Janssen AG, Fahlke C.; ''Barttin activates ClC-K channel function by modulating gating.''; PubMedEurope PMCScholia
Ambrosini L, Mercer JF.; ''Defective copper-induced trafficking and localization of the Menkes protein in patients with mild and copper-treated classical Menkes disease.''; PubMedEurope PMCScholia
Adachi K, Oiwa K, Nishizaka T, Furuike S, Noji H, Itoh H, Yoshida M, Kinosita K Jr.; ''Coupling of rotation and catalysis in F(1)-ATPase revealed by single-molecule imaging and manipulation.''; PubMedEurope PMCScholia
Lane LK, Shull MM, Whitmer KR, Lingrel JB.; ''Characterization of two genes for the human Na,K-ATPase beta subunit.''; PubMedEurope PMCScholia
Meyer-Kleine C, Steinmeyer K, Ricker K, Jentsch TJ, Koch MC.; ''Spectrum of mutations in the major human skeletal muscle chloride channel gene (CLCN1) leading to myotonia.''; PubMedEurope PMCScholia
Schaefer L, Sakai H, Mattei M, Lazdunski M, Lingueglia E.; ''Molecular cloning, functional expression and chromosomal localization of an amiloride-sensitive Na(+) channel from human small intestine.''; PubMedEurope PMCScholia
Nikolic Z, Laube B, Weber RG, Lichter P, Kioschis P, Poustka A, Mülhardt C, Becker CM.; ''The human glycine receptor subunit alpha3. Glra3 gene structure, chromosomal localization, and functional characterization of alternative transcripts.''; PubMedEurope PMCScholia
Wally J, Halbrooks PJ, Vonrhein C, Rould MA, Everse SJ, Mason AB, Buchanan SK.; ''The crystal structure of iron-free human serum transferrin provides insight into inter-lobe communication and receptor binding.''; PubMedEurope PMCScholia
Suzuki M.; ''The Drosophila tweety family: molecular candidates for large-conductance Ca2+-activated Cl- channels.''; PubMedEurope PMCScholia
Sudbrak R, Brown J, Dobson-Stone C, Carter S, Ramser J, White J, Healy E, Dissanayake M, Larrègue M, Perrussel M, Lehrach H, Munro CS, Strachan T, Burge S, Hovnanian A, Monaco AP.; ''Hailey-Hailey disease is caused by mutations in ATP2C1 encoding a novel Ca(2+) pump.''; PubMedEurope PMCScholia
Garrett KM, Duman RS, Saito N, Blume AJ, Vitek MP, Tallman JF.; ''Isolation of a cDNA clone for the alpha subunit of the human GABA-A receptor.''; PubMedEurope PMCScholia
Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW.; ''The Wilson disease gene: spectrum of mutations and their consequences.''; PubMedEurope PMCScholia
Nakashima Y, Nishimura S, Maeda A, Barsoumian EL, Hakamata Y, Nakai J, Allen PD, Imoto K, Kita T.; ''Molecular cloning and characterization of a human brain ryanodine receptor.''; PubMedEurope PMCScholia
Kim E, Youn B, Kemper L, Campbell C, Milting H, Varsanyi M, Kang C.; ''Characterization of human cardiac calsequestrin and its deleterious mutants.''; PubMedEurope PMCScholia
Marquardt A, Stöhr H, Passmore LA, Krämer F, Rivera A, Weber BH.; ''Mutations in a novel gene, VMD2, encoding a protein of unknown properties cause juvenile-onset vitelliform macular dystrophy (Best's disease).''; PubMedEurope PMCScholia
GarcÃÂa-Añoveros J, Derfler B, Neville-Golden J, Hyman BT, Corey DP.; ''BNaC1 and BNaC2 constitute a new family of human neuronal sodium channels related to degenerins and epithelial sodium channels.''; PubMedEurope PMCScholia
Ye G, Chen C, Han D, Xiong X, Kong Y, Wan B, Yu L.; ''Cloning of a novel human NHEDC1 (Na+/H+ exchanger like domain containing 1) gene expressed specifically in testis.''; PubMedEurope PMCScholia
Dulhunty AF, Pouliquin P, Coggan M, Gage PW, Board PG.; ''A recently identified member of the glutathione transferase structural family modifies cardiac RyR2 substate activity, coupled gating and activation by Ca2+ and ATP.''; PubMedEurope PMCScholia
Frattini A, Pangrazio A, Susani L, Sobacchi C, Mirolo M, Abinun M, Andolina M, Flanagan A, Horwitz EM, Mihci E, Notarangelo LD, Ramenghi U, Teti A, Van Hove J, Vujic D, Young T, Albertini A, Orchard PJ, Vezzoni P, Villa A.; ''Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis.''; PubMedEurope PMCScholia
Schatzmann HJ.; ''ATP-dependent Ca++-extrusion from human red cells.''; PubMedEurope PMCScholia
Turi JL, Wang X, McKie AT, Nozik-Grayck E, Mamo LB, Crissman K, Piantadosi CA, Ghio AJ.; ''Duodenal cytochrome b: a novel ferrireductase in airway epithelial cells.''; PubMedEurope PMCScholia
Swoboda KJ, Kanavakis E, Xaidara A, Johnson JE, Leppert MF, Schlesinger-Massart MB, Ptacek LJ, Silver K, Youroukos S.; ''Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation.''; PubMedEurope PMCScholia
Neagoe I, Stauber T, Fidzinski P, Bergsdorf EY, Jentsch TJ.; ''The late endosomal ClC-6 mediates proton/chloride countertransport in heterologous plasma membrane expression.''; PubMedEurope PMCScholia
Yang W, Drewe JA, Lan NC.; ''Cloning and characterization of the human GABAA receptor alpha 4 subunit: identification of a unique diazepam-insensitive binding site.''; PubMedEurope PMCScholia
Kieferle S, Fong P, Bens M, Vandewalle A, Jentsch TJ.; ''Two highly homologous members of the ClC chloride channel family in both rat and human kidney.''; PubMedEurope PMCScholia
Cid LP, Montrose-Rafizadeh C, Smith DI, Guggino WB, Cutting GR.; ''Cloning of a putative human voltage-gated chloride channel (CIC-2) cDNA widely expressed in human tissues.''; PubMedEurope PMCScholia
de Carvalho Aguiar P, Sweadner KJ, Penniston JT, Zaremba J, Liu L, Caton M, Linazasoro G, Borg M, Tijssen MA, Bressman SB, Dobyns WB, Brashear A, Ozelius LJ.; ''Mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 are associated with rapid-onset dystonia parkinsonism.''; PubMedEurope PMCScholia
Quigley JG, Yang Z, Worthington MT, Phillips JD, Sabo KM, Sabath DE, Berg CL, Sassa S, Wood BL, Abkowitz JL.; ''Identification of a human heme exporter that is essential for erythropoiesis.''; PubMedEurope PMCScholia
Scholl U, Hebeisen S, Janssen AG, Müller-Newen G, Alekov A, Fahlke C.; ''Barttin modulates trafficking and function of ClC-K channels.''; PubMedEurope PMCScholia
Donier E, Rugiero F, Jacob C, Wood JN.; ''Regulation of ASIC activity by ASIC4--new insights into ASIC channel function revealed by a yeast two-hybrid assay.''; PubMedEurope PMCScholia
Schofield PR, Pritchett DB, Sontheimer H, Kettenmann H, Seeburg PH.; ''Sequence and expression of human GABAA receptor alpha 1 and beta 1 subunits.''; PubMedEurope PMCScholia
Oakhill JS, Marritt SJ, Gareta EG, Cammack R, McKie AT.; ''Functional characterization of human duodenal cytochrome b (Cybrd1): Redox properties in relation to iron and ascorbate metabolism.''; PubMedEurope PMCScholia
Qu Z, Hartzell HC.; ''Bestrophin Cl- channels are highly permeable to HCO3-.''; PubMedEurope PMCScholia
Leisle L, Ludwig CF, Wagner FA, Jentsch TJ, Stauber T.; ''ClC-7 is a slowly voltage-gated 2Cl(-)/1H(+)-exchanger and requires Ostm1 for transport activity.''; PubMedEurope PMCScholia
Richardson DR, Lane DJ, Becker EM, Huang ML, Whitnall M, Suryo Rahmanto Y, Sheftel AD, Ponka P.; ''Mitochondrial iron trafficking and the integration of iron metabolism between the mitochondrion and cytosol.''; PubMedEurope PMCScholia
Hadingham KL, Garrett EM, Wafford KA, Bain C, Heavens RP, Sirinathsinghji DJ, Whiting PJ.; ''Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors.''; PubMedEurope PMCScholia
Keryanov S, Gardner KL.; ''Physical mapping and characterization of the human Na,K-ATPase isoform, ATP1A4.''; PubMedEurope PMCScholia
Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW.; ''The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene.''; PubMedEurope PMCScholia
Vanmolkot KR, Kors EE, Hottenga JJ, Terwindt GM, Haan J, Hoefnagels WA, Black DF, Sandkuijl LA, Frants RR, Ferrari MD, van den Maagdenberg AM.; ''Novel mutations in the Na+, K+-ATPase pump gene ATP1A2 associated with familial hemiplegic migraine and benign familial infantile convulsions.''; PubMedEurope PMCScholia
Wagstaff J, Chaillet JR, Lalande M.; ''The GABAA receptor beta 3 subunit gene: characterization of a human cDNA from chromosome 15q11q13 and mapping to a region of conserved synteny on mouse chromosome 7.''; PubMedEurope PMCScholia
Suzuki M, Mizuno A.; ''A novel human Cl(-) channel family related to Drosophila flightless locus.''; PubMedEurope PMCScholia
Wakabayashi K, Nakagawa H, Tamura A, Koshiba S, Hoshijima K, Komada M, Ishikawa T.; ''Intramolecular disulfide bond is a critical check point determining degradative fates of ATP-binding cassette (ABC) transporter ABCG2 protein.''; PubMedEurope PMCScholia
Petris MJ, Mercer JF.; ''The Menkes protein (ATP7A; MNK) cycles via the plasma membrane both in basal and elevated extracellular copper using a C-terminal di-leucine endocytic signal.''; PubMedEurope PMCScholia
Tandy S, Williams M, Leggett A, Lopez-Jimenez M, Dedes M, Ramesh B, Srai SK, Sharp P.; ''Nramp2 expression is associated with pH-dependent iron uptake across the apical membrane of human intestinal Caco-2 cells.''; PubMedEurope PMCScholia
Vanoevelen J, Dode L, Van Baelen K, Fairclough RJ, Missiaen L, Raeymaekers L, Wuytack F.; ''The secretory pathway Ca2+/Mn2+-ATPase 2 is a Golgi-localized pump with high affinity for Ca2+ ions.''; PubMedEurope PMCScholia
Chelly J, Tümer Z, Tønnesen T, Petterson A, Ishikawa-Brush Y, Tommerup N, Horn N, Monaco AP.; ''Isolation of a candidate gene for Menkes disease that encodes a potential heavy metal binding protein.''; PubMedEurope PMCScholia
Hadingham KL, Wingrove P, Le Bourdelles B, Palmer KJ, Ragan CI, Whiting PJ.; ''Cloning of cDNA sequences encoding human alpha 2 and alpha 3 gamma-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant alpha 1-, alpha 2-, alpha 3-, and alpha 5-containing human gamma-aminobutyric acidA receptors.''; PubMedEurope PMCScholia
de Weille JR, Bassilana F, Lazdunski M, Waldmann R.; ''Identification, functional expression and chromosomal localisation of a sustained human proton-gated cation channel.''; PubMedEurope PMCScholia
Niesler B, Walstab J, Combrink S, Möller D, Kapeller J, Rietdorf J, Bönisch H, Göthert M, Rappold G, Brüss M.; ''Characterization of the novel human serotonin receptor subunits 5-HT3C,5-HT3D, and 5-HT3E.''; PubMedEurope PMCScholia
Calcraft PJ, Ruas M, Pan Z, Cheng X, Arredouani A, Hao X, Tang J, Rietdorf K, Teboul L, Chuang KT, Lin P, Xiao R, Wang C, Zhu Y, Lin Y, Wyatt CN, Parrington J, Ma J, Evans AM, Galione A, Zhu MX.; ''NAADP mobilizes calcium from acidic organelles through two-pore channels.''; PubMedEurope PMCScholia
Willingham MC, Hanover JA, Dickson RB, Pastan I.; ''Morphologic characterization of the pathway of transferrin endocytosis and recycling in human KB cells.''; PubMedEurope PMCScholia
Miyake A, Mochizuki S, Takemoto Y, Akuzawa S.; ''Molecular cloning of human 5-hydroxytryptamine3 receptor: heterogeneity in distribution and function among species.''; PubMedEurope PMCScholia
Shull MM, Pugh DG, Lingrel JB.; ''Characterization of the human Na,K-ATPase alpha 2 gene and identification of intragenic restriction fragment length polymorphisms.''; PubMedEurope PMCScholia
Meij IC, Koenderink JB, van Bokhoven H, Assink KF, Groenestege WT, de Pont JJ, Bindels RJ, Monnens LA, van den Heuvel LP, Knoers NV.; ''Dominant isolated renal magnesium loss is caused by misrouting of the Na(+),K(+)-ATPase gamma-subunit.''; PubMedEurope PMCScholia
Wang D, King SM, Quill TA, Doolittle LK, Garbers DL.; ''A new sperm-specific Na+/H+ exchanger required for sperm motility and fertility.''; PubMedEurope PMCScholia
Wingrove P, Hadingham K, Wafford K, Kemp JA, Ragan CI, Whiting P.; ''Cloning and expression of a cDNA encoding the human GABA-A receptor alpha 5 subunit.''; PubMedEurope PMCScholia
Schimanski LM, Drakesmith H, Merryweather-Clarke AT, Viprakasit V, Edwards JP, Sweetland E, Bastin JM, Cowley D, Chinthammitr Y, Robson KJ, Townsend AR.; ''In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations.''; PubMedEurope PMCScholia
Hara-Chikuma M, Yang B, Sonawane ND, Sasaki S, Uchida S, Verkman AS.; ''ClC-3 chloride channels facilitate endosomal acidification and chloride accumulation.''; PubMedEurope PMCScholia
Cutting GR, Curristin S, Zoghbi H, O'Hara B, Seldin MF, Uhl GR.; ''Identification of a putative gamma-aminobutyric acid (GABA) receptor subunit rho2 cDNA and colocalization of the genes encoding rho2 (GABRR2) and rho1 (GABRR1) to human chromosome 6q14-q21 and mouse chromosome 4.''; PubMedEurope PMCScholia
Malik N, Canfield VA, Beckers MC, Gros P, Levenson R.; ''Identification of the mammalian Na,K-ATPase 3 subunit.''; PubMedEurope PMCScholia
Kawakami K, Ohta T, Nojima H, Nagano K.; ''Primary structure of the alpha-subunit of human Na,K-ATPase deduced from cDNA sequence.''; PubMedEurope PMCScholia
Hu Z, Bonifas JM, Beech J, Bench G, Shigihara T, Ogawa H, Ikeda S, Mauro T, Epstein EH Jr.; ''Mutations in ATP2C1, encoding a calcium pump, cause Hailey-Hailey disease.''; PubMedEurope PMCScholia
Harding C, Heuser J, Stahl P.; ''Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes.''; PubMedEurope PMCScholia
Sato M, Schilsky ML, Stockert RJ, Morell AG, Sternlieb I.; ''Detection of multiple forms of human ceruloplasmin. A novel Mr 200,000 form.''; PubMedEurope PMCScholia
Dong XP, Cheng X, Mills E, Delling M, Wang F, Kurz T, Xu H.; ''The type IV mucolipidosis-associated protein TRPML1 is an endolysosomal iron release channel.''; PubMedEurope PMCScholia
Birkenhäger R, Otto E, Schürmann MJ, Vollmer M, Ruf EM, Maier-Lutz I, Beekmann F, Fekete A, Omran H, Feldmann D, Milford DV, Jeck N, Konrad M, Landau D, Knoers NV, Antignac C, Sudbrak R, Kispert A, Hildebrandt F.; ''Mutation of BSND causes Bartter syndrome with sensorineural deafness and kidney failure.''; PubMedEurope PMCScholia
Ovchinnikov YuA, Monastyrskaya GS, Broude NE, Ushkaryov YuA, Melkov AM, Smirnov YuV, Malyshev IV, Allikmets RL, Kostina MB, Dulubova IE.; ''Family of human Na+, K+-ATPase genes. Structure of the gene for the catalytic subunit (alpha III-form) and its relationship with structural features of the protein.''; PubMedEurope PMCScholia
Price MP, Snyder PM, Welsh MJ.; ''Cloning and expression of a novel human brain Na+ channel.''; PubMedEurope PMCScholia
Ma JY, Song YH, Sjöstrand SE, Rask L, Mårdh S.; ''cDNA cloning of the beta-subunit of the human gastric H,K-ATPase.''; PubMedEurope PMCScholia
Dierick HA, Adam AN, Escara-Wilke JF, Glover TW.; ''Immunocytochemical localization of the Menkes copper transport protein (ATP7A) to the trans-Golgi network.''; PubMedEurope PMCScholia
Schlingmann KP, Konrad M, Jeck N, Waldegger P, Reinalter SC, Holder M, Seyberth HW, Waldegger S.; ''Salt wasting and deafness resulting from mutations in two chloride channels.''; PubMedEurope PMCScholia
Melis D, Havelaar AC, Verbeek E, Smit GP, Benedetti A, Mancini GM, Verheijen F.; ''NPT4, a new microsomal phosphate transporter: mutation analysis in glycogen storage disease type Ic.''; PubMedEurope PMCScholia
Bailey ME, Albrecht BE, Johnson KJ, Darlison MG.; ''Genetic linkage and radiation hybrid mapping of the three human GABA(C) receptor rho subunit genes: GABRR1, GABRR2 and GABRR3.''; PubMedEurope PMCScholia
Campbell HD, Kamei M, Claudianos C, Woollatt E, Sutherland GR, Suzuki Y, Hida M, Sugano S, Young IG.; ''Human and mouse homologues of the Drosophila melanogaster tweety (tty) gene: a novel gene family encoding predicted transmembrane proteins.''; PubMedEurope PMCScholia
Ohgami RS, Campagna DR, Greer EL, Antiochos B, McDonald A, Chen J, Sharp JJ, Fujiwara Y, Barker JE, Fleming MD.; ''Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells.''; PubMedEurope PMCScholia
Heise CJ, Xu BE, Deaton SL, Cha SK, Cheng CJ, Earnest S, Sengupta S, Juang YC, Stippec S, Xu Y, Zhao Y, Huang CL, Cobb MH.; ''Serum and glucocorticoid-induced kinase (SGK) 1 and the epithelial sodium channel are regulated by multiple with no lysine (WNK) family members.''; PubMedEurope PMCScholia
Doyle L, Ross DD.; ''Multidrug resistance mediated by the breast cancer resistance protein BCRP (ABCG2).''; PubMedEurope PMCScholia
Zhu Y, Ripps H, Qian H.; ''A single amino acid in the second transmembrane domain of GABA rho receptors regulates channel conductance.''; PubMedEurope PMCScholia
Grishin AV, Sverdlov VE, Kostina MB, Modyanov NN.; ''Cloning and characterization of the entire cDNA encoded by ATP1AL1--a member of the human Na,K/H,K-ATPase gene family.''; PubMedEurope PMCScholia
Han O, Kim EY.; ''Colocalization of ferroportin-1 with hephaestin on the basolateral membrane of human intestinal absorptive cells.''; PubMedEurope PMCScholia
Hadingham KL, Wingrove PB, Wafford KA, Bain C, Kemp JA, Palmer KJ, Wilson AW, Wilcox AS, Sikela JM, Ragan CI.; ''Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors.''; PubMedEurope PMCScholia
Tsunenari T, Sun H, Williams J, Cahill H, Smallwood P, Yau KW, Nathans J.; ''Structure-function analysis of the bestrophin family of anion channels.''; PubMedEurope PMCScholia
Shayeghi M, Latunde-Dada GO, Oakhill JS, Laftah AH, Takeuchi K, Halliday N, Khan Y, Warley A, McCann FE, Hider RC, Frazer DM, Anderson GJ, Vulpe CD, Simpson RJ, McKie AT.; ''Identification of an intestinal heme transporter.''; PubMedEurope PMCScholia
Ohgami RS, Campagna DR, McDonald A, Fleming MD.; ''The Steap proteins are metalloreductases.''; PubMedEurope PMCScholia
Rey MA, Duffy SP, Brown JK, Kennedy JA, Dick JE, Dror Y, Tailor CS.; ''Enhanced alternative splicing of the FLVCR1 gene in Diamond Blackfan anemia disrupts FLVCR1 expression and function that are critical for erythropoiesis.''; PubMedEurope PMCScholia
The ferritin complex is an oligomer of 24 subunits with light and heavy chains. The major chain can be light or heavy, depending on the tissue type. The functional molecule forms a roughly spherical shell with a diameter of 12 nm and contains a central cavity into which the insoluble mineral iron core is deposited. Iron metabolism provides a useful example of gene expression translational control. Increased iron levels stimulate the synthesis of the iron-binding protein, ferritin, without any corresponding increase in the amount of ferritin mRNA. The 5?-UTR of both ferritin heavy chain mRNA and light chain mRNA contain a single iron-response element (IRE), a specific cis-acting regulatory sequence which forms a hairpin structure.
Ferritin oxidises Fe(II) ions to Fe(III), migrates them to its centre, and collects thousands of them as FeO(OH) in the central mineral core from which they can be later remobilised (Harrison & Arrosio 1996).
The plasma membrane contains a broad range of lipids making up the bilayer. Aminophospholipids (APLs) such as phosphatidylserine (PS) and phosphatidylethanolamine (PE) are distributed in this bilayer and their arrangement is mediated by the P-type ATPases type IV family (Paulusma and Oude Elferink, 2005).
Many Cl- channels such as CFTR, ClC, CaCC, and ligand-gated anion channels are permeable to bicarbonate (HCO3-) which is an important anion in the regulation of pH. Many tissues, including retinal pigment epithelium (RPE), utilize HCO3- transporters to mediate transport of HCO3-. Bestrophns 1-4 (BEST1-4, aka vitelliform macular dystrophy proteins) have high permeability to HCO3- (Hu & Hartzell 2008). Defective BEST1 may play a role in macular degeneration in the eye due to impaired HCO3- and Cl- conductance (Hu & Hartzell 2008).
The microsomal Na+/(PO4)3- transporter isoform 1 (SLC17A3, NPT4 isoform 1) is a member of the anion-cation symporter family. It is expressed in liver, kidney and intestine and may function as a cotransporter of sodium (Na+) and phosphate ((PO4)3- or Pi) across the ER membrane (Melis et al. 2004).
Amiloride-sensitive sodium channels (SCNNs, aka ENaCs, epithelial Na+ channels, non voltage-gated sodium channels) belong to the epithelial Na+ channel/degenerin (ENaC/DEG) protein family and mediate the transport of Na+ (and associated water) through the apical membrane of epithelial cells in kidney, colon and lungs. This makes SCNNs important determinants of systemic blood pressure. The physiological activator for SCNNs is unknown but as they belong in the same family as acid-sensitive ion channels (ASICs, which are mediated by protons), these may also be the activating ligands for SCNNs. SCNNs are probable heterotrimers comprising an alpha (or interchangeable delta subunit), beta and gamma subunit (Horisberger 1998).
Human serum urate levels are largely maintained by its reabsorption and secretion in the kidney. Loss of this maintenance can elevate urate levels leading to gout, hypertension, and various cardiovascular diseases. Renal urate reabsorption is controlled via two proximal tubular urate transporters; apical SLC22A12 (URAT1) and basolateral SLC2A9 (URATv1, GLUT9). On the other hand, urate secretion is mediated by the orphan sodium phosphate transporter 4 isoform 2 (SLC17A3, NPT4 isoform 2). It is mainly expressed at the apical side of renal tubules and functions as a voltage-driven urate transporter (Jutabha et al. 2010).
Genetic variations in SLC17A3 influence the variance in serum uric acid concentrations and define the serum uric acid concentration quantitative trait locus 4 (UAQTL4; MIM:612671). Excess serum urate (hyperuricemia) can lead to the development of gout, characterized by tissue deposition of monosodium urate crystals.
Chloride channel proteins 1, 2, Ka and Kb (CLCN1, 2, KA, KB) can mediate Cl- influx across the plasma membrane of almost all cells. CLCN1 is expressed mainly on skeletal muscle where it is involved in the electrical stability of the muscle. CLCN1 is thought to function in a homotetrameric form (Steimeyer et al. 1994). CLCN2 is ubiquitously expressed, playing a role in the regulation of cell volume (Cid et al. 1995, Niemeyer et al. 2009). Defects in CLCN1 cause myotonia congenita, an autosomal dominant disease (MCD aka Thomsen disease, MIM:160800). It is characterized by muscle stiffness due to delayed relaxation, resulting from membrane hyperexcitability (Meyer-Kleine et al. 1995, Steimeyer et al. 1994). Defects in CLCN1 also cause autosomal recessive myotonia congenita (MCR aka Becker disease, MIM:255700) (Koch et al. 1992, Meyer-Kleine et al. 1995), a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Becker disease is more common and more severe than Thomsen disease.
CLCNKA and B (Kieferle et al. 1994) are predominantly expressed in distal nephron segments of the kidney (Takeuchi et al. 1995) and the inner ear (Estevez et al. 2001, Schlingmann et al. 2004). They are tightly associated with their essential beta subunit barttin (BSND), requiring it to be fully functional channels (Fischer et al. 2010, Scholl et al. 2006). These channels bound to BSND are essential for renal Cl- reabsorption (Waldegger & Jentsch 2000) and K+ recycling in the inner ear (Estevez et al. 2001). Defects in CLCNKA and B cause Bartter syndrome type 4B (BS4B; MIM:613090) characterized by impaired salt reabsorption and sensorineural deafness (Schlingmann et al. 2004, Nozu et al. 2008). Defects in BSND cause Bartter syndrome type 4A (BS4A aka infantile Bartter syndrome with sensorineural deafness; MIM:602522) characterized by impaired salt reabsorption in the thick ascending loop of Henle and sensorineural deafness (Birkenhager et al. 2001, Nozu et al. 2008).
The H+/Cl- exchange transporter CLCN3 (Borsani et al. 1995) mediates the exchange of endosomal Cl- for cytosolic H+ across late endosomal membranes, contributing to the acidification of endosomes. The activity of CLCN3 is inferred from experiments in mice (Stobrawa et al. 2001, Hara-Chikuma et al. 2005).
The sodium leak channel non-selective protein NALCN, a nonselective cation channel, forms the background Na+ leak conductance and controls neuronal excitability (Lu et al. 2007). Mice with mutant NALCN have a severely disrupted respiratory rhythm and die within 24 hours of birth. Calcium (Ca2+) influences neuronal excitability via the NALCN:UNC79:UNC80 complex, with high Ca2+ concentrations inhibiting transport of Na+ (Lu et al. 2010).
Protein tweety homolog 1 (TTYH1) has 5 isoforms. Isoform 3 (Campbell et al. 2000) mediates the Ca+-independent efflux of Cl- across plasma membranes (Suzuki & Mizuno 2004, Suzuki 2006).
Ryanodine receptors (RYRs) are located in the sarcoplasmic reticulum (SR) membrane and mediate the release of Ca2+ from intracellular stores during excitation-contraction (EC) coupling in both cardiac and skeletal muscle. RYRs are the largest known ion channels (>2MDa) and are functional in their homotetrameric forms. There are three mammalian isoforms (RYR1-3); RYR1 is prominent in skeletal muscle (Zorzato et al. 1990), RYR2 in cardiac muscle (Tunwell et al. 1996) and RYR3 is found in the brain (Nakashima et al. 1997). For review see Lanner et al. 2010. The function of RYRs are controlled by intracellular Ca2+-binding proteins calsequestrin 1 and 2 (CASQ1 and 2) and the anchoring proteins triadin (TRDN) and junctin. Together, they make up the Ca2+-release complex. CASQ1 and 2 buffer intra-SR Ca2+ stores in skeletal muscle and cardiac muscle respectively (Fujii et al. 1990, Kim et al. 2007). When Ca2+ concentrations reach 1mM, CASQs polymerize (Kim et al. 2007) and can attach to one end of RYRs, mediated by anchoring proteins TRDN and junctin (Taske et al. 1995). By sequestering Ca2+ ions, CASQs can inhibit RYRs function. For reviews see Beard et al. 2004, Beard et al. 2009a, Beard et al. 2009b.
A member of the intracellular Cl- channel protein family, CLIC2, has also been determined to inhibit RYR-mediated Ca2+ transport (Board et al. 2004), potentially playing a role in the homeostasis of Ca2+ release from intracellular stores. Inhibition is thought to be via reducing activation of the channels by their primary endogenous cytoplasmic ligands, ATP and Ca2+ (Dulhunty et al. 2005).
Bestrophins 1-4 (BEST1-4, aka vitelliform macular dystrophy proteins) mediate cytosolic Cl- efflux across plasma membranes. This transport is sensitive to intracellular Ca2+ concentrations (Sun et al. 2002, Tsunenari et al. 2003). Mutations in bestrophins that impair their function are implicated in macular degeneration in the eye. Defects in BEST1 cause vitelliform macular dystrophy (BVMD, Best's disease, MIM:153700), an autosomal dominant form of macular degeneration that usually begins in childhood and is characterized lesions due to abnormal accumulation of lipofuscin within and beneath retinal pigment epithelium (RPE) cells (Marquardt et al. 1998, Petrukhin et al. 1998).
The sperm-specific Na+/H+ exchanger SLC9C1 (aka sodium/hydrogen exchanger 10, NHE10) is localized to the flagellar membrane and is involved in pH regulation of spermatozoa required for sperm motility and fertility. The activity of human SLC9C1 is inferred from experiments using mouse Slc9c1 (Wang et al. 2003).
Acid-sensing ion channels 1, 2, 3 and 5 (ASIC1, 2, 3 and 5, aka amiloride-sensitive cation channels) are homotrimeric, multi-pass membrane proteins which can transport sodium (Na+) when activated by extracellular protons. Members of the ASIC family are sensitive to amiloride and function in neurotransmission. The encoded proteins function in learning, pain transduction, touch sensation, and development of memory and fear. Many neuronal diseases cause acidosis, accompanied by pain and neuronal damage; ASICs can mediate the pathophysiological effects seen in acidiosis (Wang & Xu 2011, Qadri et al. 2012). The diuretic drug amiloride inhibits these channels, resulting in analgesic effects. NSAIDs (Nonsteroidal anti-inflammatory drugs) can also inhibit ASICs to produce analgesia (Voilley et al. 2001). ASICs are also partially permeable to Ca2+, Li+ and K+ (not shown here). ASIC1 and 2 are expressed mostly in brain (Garcia-Anoveros et al. 1997, Price et al. 1996), ASIC3 is strongly expressed in testis (de Weille et al. 1998, Ishibashi & Marumo 1998) and ASIC5 is found mainly in intestine (Schaefer et al. 2000). ASIC4 subunits do not form functional channels and it's activity is unknown. It could play a part in regulating other ASIC activity (Donier et al. 2008).
Chloride channel 7 comprises H+/Cl- exchange transporter 7 (CLCN7) and osteopetrosis-associated transmembrane protein 1 (OSTM1) (Leisle et al. 2011). This complex localises to the lysosomal membrane where it mediates the exchange of Cl- and H+ ions, perhaps playing a role in the acidification of the lysosome (Graves et al. 2008).
Defects in CLCN7 cause osteopetrosis autosomal recessive types 2 and 4 (OPTB2, MIM:166600 and OPTB4, MIM:611490) (Frattini et al. 2003, Pangrazio et al. 2010). Defects in OSTM1 cause osteopetrosis autosomal recessive type 5 (OPTB5, MIM:259720) (Pangrazio et al. 2006).
Mitochondrial sodium/hydrogen exchanger 9B2 (SLC9B2, aka NHA2) is ubiquitously expressed and mediates the electrogenic exchange of 1 Na+ (or 1 Li+) for 2 H+ across the inner mitochondrial membrane (Xiang et al. 2007, Taglicht et al. 1993). This transport is thought to play a role in salt homeostasis and pH regulation in humans.
Amiloride-sensitive sodium channels (SCNNs, aka ENaCs, epithelial Na+ channels, non voltage-gated sodium channels) comprises three subunits (alpha, beta and gamma) and plays an essential role in Na+ and fluid absorption in the kidney, colon and lung. The number of channels at the cell's surface (consequently its function) can be regulated. This is achieved by ubiquitination of SCNN via E3 ubiquitin-protein ligases (NED4L and WPP1) (Staub et al. 2000, Farr et al. 2000). NED4L/WPP1 is found in a signaling complex including Raf1 (RAF proto-oncogene serine/threonine-protein kinase), SGK (serum/glucocorticoid-regulated kinase) and GILZ (glucocorticoid-induced leucine zipper protein, TSC22D3) (Soundararajan et al. 2009). Ubiquitinated SCNN (Ub-SCNN) is targeted for degradation so a lesser number of channels are present at the cell surface, reducing the amount of Na+ absorption. Proline-rich sequences at the C-terminus of SCNNs include the PY motif containing a PPxY sequence. PY motifs bind WW domains of NED4L/WPP1. Protein kinases with no lysine K (WNKs) can activate SCNN activity by interacting non-enzymatically with the signaling complex, specifically SGK although the mechanism is unknown (Heise et al. 2010).
Human homologues 2 and 3 (TTYH2 and 3) mediate the efflux of Cl- from cells in response to the increase in intracellular Ca2+ levels (Suzuki & Mizuno 2004, Suzuki 2006).
The H+/Cl- exchange transporters CLCN4 (Kawasaki et al. 1999, Zdebik et al. 2008), CLCN5 (Zdebik et al. 2008) and CLCN6 (Neagoe et al. 2010) mediate the exchange of endosomal Cl- for cytosolic H+ across endosomal membranes, contributing to the acidification of endosomes.
Calcium (Ca2+) can be mobilised from intracellular stores by the presence of nicotinic acid adenine dinucleotide phosphate (NAADP). Two pore calcium channel proteins 1 and 2 (TPCN1 and 2) are expressed on endosomal (not shown here) and lysosomal membranes and mediate the mobilization of Ca2+ from these organelles when activated by NAADP (Brailoiu et al. 2009, Calcraft et al. 2009).
Calcium-activated chloride channels (CaCCs) are ubiquitously expressed and implicated in physiological processes such as sensory transduction, fertilization, epithelial secretion, and smooth muscle contraction. The anoctamin family of transmembrane proteins (ANO, TMEM16) belong to CaCCs and have been shown to transport Cl- ions when activated by intracellular Ca2+ (Galietta 2009, Huang et al. 2012). There are currently 10 members, ANO1-10, all having a similar structure, with eight putative transmembrane domains and cytosolic amino- and carboxy-termini. ANO1 and 2 possess Ca2+ activated Cl- transport activity (Yang et al. 2008, Scudieri et al. 2012) while the remaining members also show some demonstrable activity (Tian et al. 2012).
The sodium/hydrogen exchanger 9B1 (SLC9B1 aka Na+/H+ exchanger like domain containing 1, NHEDC1) is specifically expressed on the plasma membrane of the testis and may be implicated in infertility (Ye et al. 2006). Sodium/hydrogen exchanger 9C2 (SLC9C2), also localized to the plasma membrane, may be involved in pH regulation although this protein has not been fully characterized.
The primary site for absorption of dietary iron is the duodenum. Ferrous iron (Fe2+) is taken up from the gut lumen across the apical membranes of enterocytes and released into the portal vein circulation across basolateral membranes. The human gene SLC11A2 encodes the divalent cation transporter DCT1 (NRAMP2, Natural resistance-associated macrophage protein 2). NRAMP2 resides on the apical membrane of enterocytes and mediates the uptake of ferrous iron into these cells (Tandy S et al, 2000). DCT1 can also accept a broad range of transition metal ions.
The primary site for absorption of dietary iron is the duodenum. Ferrous iron (Fe2+) is taken up from the gut lumen across the apical membranes of enterocytes and released into the portal vein circulation across basolateral membranes. The human gene SLC40A1 encodes a metal transporter protein MTP1 (also called ferroportin or IREG1). This protein resides on the basolateral membrane of enterocytes and mediates ferrous iron efflux into the portal vein (Schimanski LM et al, 2005). MTP1 colocalizes with hephaestin (HEPH) which stablizes MTP1 and is necessary for the efflux reaction to occur (Han O and Kim EY, 2007; Chen H et al, 2009). As well as the dudenum, MTP1 is also highly expressed on macrophages (where it mediates iron efflux from the breakdown of haem) and the placenta (where it may mediate the transport of iron from maternal to foetal circulation). It is also expressed in muscle and spleen.
Heme oxygenase (HO) cleaves the heme ring at the alpha-methene bridge to form bilverdin. This reaction forms the only endogenous source of carbon monoxide. HO-1 is inducible and is thought to have an antioxidant role as it's activated in virtually all cell types and by many types of "oxidative stress" (Poss and Tonegawa, 1997). HO-2 is non-inducible.
Intracellular pools of Ca2+ serve as the source for inositol 1,4,5-trisphosphate (IP3) -induced alterations in cytoplasmic free Ca2+. In most human cells Ca2+ is stored in the lumen of the sarco/endoplastic reticulum by ATPases known as SERCAs (ATP2As). In platelets, ATP2As transport Ca2+ into the platelet dense tubular network. ATP2As are P-type ATPases, similar to the plasma membrane Na+ and Ca+-ATPases. Humans have three genes for SERCA pumps; ATP2A1-3. Studies on ATP2A1 suggest that it binds two Ca2+ ions from the cytoplasm and is subsequently phosphorylated at Asp351 before translocating Ca2+ into the SR lumen. There is a counter transport of two or possibly three protons ensuring partial charge balancing.
The plasma membrane Ca-ATPases 1-4 (ATP2B1-4, PMCAs) are P-type Ca2+-ATPases regulated by calmodulin. The PMCA also counter-transports a proton. PMCA is important for Ca2+ homeostasis and function.
MTP1 is also highly expressed on macrophages where it mediates iron efflux from the breakdown of haem. The human gene SLC40A1 encodes a metal transporter protein MTP1 (also called ferroportin or IREG1) (Schimanski LM et al, 2005). MTP1 colocalizes with ceruloplasmin (CP) which stablizes MTP1 and is necessary for the efflux reaction to occur (Texel SJ et al, 2008). Ceruloplasmin also catalyzes the conversion of iron from ferrous (Fe2+) to ferric form (Fe3+), therefore assisting in its transport in the plasma in association with transferrin, which can only carry iron in the ferric state. As well as on macrophages, MTP1 is also highly expressed in the duodenum, placenta (where it may mediate the transport of iron from maternal to foetal circulation), in muscle and the spleen.
The iron ions that are no longer bound to transferrin are reduced by the metalloreductase STEAP3, an endosomal membrane protein. The electron donor partner of the enzyme is unknown (Ohgami et al, 2005; Ohgami et al, 2006).
After about 15 minutes on the cell surface, the equilibrium favors dissociation of transferrin, and the transferrin receptor 1 dimer is available again for binding (Hemadi et al., 2006).
Transferrin receptor 1 molecules can be found on the outside of any cell. Transferrin transports two iron ions through the blood and two transferrins bind to a TfR1 dimer (West et al, 2001).
The human gene ATP7B encodes the copper-transporting ATPase 2 (ATP7B, ATPase2, Wilson's protein) which is expressed mainly in the liver, brain and kidneys (Bull et al, 1993). ATP7B resides on the trans-Golgi membrane where it it thought to sequester copper from the cytosol into the golgi (Yang et al, 1997). Defects in ATP7B are the cause of Wilson disease (WD), an autosomal recessive disorder of copper metabolism characterized by the toxic accumulation of copper in a number of organs, particularly the liver and brain (Thomas et al, 1995).
The plasma membrane contains a broad range of lipids making up the bilayer. Aminophospholipids such as phosphatidylserine (PS) and phosphatidylethanolamine (PE) are distributed in this bilayer and their arrangement is mediated by the P-type ATPases type IV family (Paulusma and Oude Elferink, 2005).
Uptake of iron from meat happens in the form of ferriheme, and via the same transporter that is used for folate. The process is more effective than taking up iron ions (Shayeghi M et al, 2005).
Mucolipin-1 is an iron ion channel specifically expressed in endosome and lysosome membranes. It catalyzes the diffusion of Fe2+ ions into the cytosol (Dong et al, 2008).
The human gene ATP7A (MNK) encodes the copper-transporting ATPase 1 (ATP7A, ATPase1, Menkes protein) which is expressed in most tissues except the liver (Vulpe et al, 1993; Chelly et al, 1993). Normally, ATP7A resides on the trans-Golgi membrane (Dierick et al, 1997). When cells are exposed to excessive copper levels, it is rapidly relocalized to the plasma membrane where it functions in copper efflux (Petris and Mercer, 1999). Defects in ATP7A are the cause of Menkes disease (MNKD), an X-linked recessive disorder of copper metabolism characterized by generalized copper deficiency (Ambrosini and Mercer, 1999).
Cytochrome b reductase 1 not only reduces ferrous iron in the brush-border membrane but also in the airways. It is upregulated on iron starvation. However, its electron donor molecule is still unknown (Oakhill et al, 2007; Turi et al, 2006).
The GABA(A) receptor (GABR) family belongs to the ligand-gated ion channel superfamily (LGIC). Its endogenous ligand is gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the central nervous system. There are six alpha subunits (GABRA) (Garrett et al. 1988, Schofield et al. 1989, Hadingham et al. 1993, Edenberg et al. 2004, Hadingham et al. 1993, Yang et al. 1995, Wingrove et al. 1992, Hadingham et al. 1996), three beta subunits (GABRB) (Schofield et al. 1989, Hadingham et al. 1993, Wagstaff et al. 1991) and 2 gamma subunits (GABRG) (Khan et al. 1993, Hadingham et al. 1995) characterized. GABA(A) functions as a heteropentamer, the most common structure being 2 alpha subunits, 2 beta subunits and a gamma subunit (2GABRA:2GABRB:GABRG). Upon binding of GABA, this complex conducts chloride ions through its pore, resulting in hyperpolarization of the neuron. This causes an inhibitory effect on neurotransmission by reducing the chances of a successful action potential occurring.
The efflux pump ABCG2 can relieve cells from toxic heme concentrations even against a concentration gradient. It is expressed in placenta, liver, and small intestine (Krishnamurthy et al, 2004; Doyle & Ross, 2003; Zhang et al, 2003).
The potassium-transporting ATPase heterodimer (ATP4A/12A:ATP4B) catalyzes the hydrolysis of ATP coupled with the exchange of H+ and K+ ions across the plasma membrane. It is composed of alpha and beta chains. Two human genes encode the catalytic alpha subunit, ATP4A and ATP12A (Maeda et al, 1990; Grishin et al, 1994). ATP4A is responsible for acid production in the stomach. ATP12A is responsible for potassium absorption in various tissues. One human gene encodes the beta subunit, ATP4B (Ma et al, 1991).
The heme transporter FLVCR is expressed in intestine and liver tissue, but also in developing erythroid cells where it is required to protect them from heme toxicity (Quigley et al, 2004; Rey et al, 2008).
The 5-hydroxytryptamine receptor (HTR3) family are members of the superfamily of ligand-gated ion channels (LGICs). Five receptors (HTR3A-E) form a heteropentamer. Binding of the neurotransmitter 5-hydroxytryptamine (5HT, serotonin) to the HTR3 complex opens the channel, which in turn, leads to an excitatory response in neurons and is permeable to sodium, potassium, and calcium ions (Miyake et al. 1995, Davies et al. 1999, Niesler et al. 2007).
The function of V-type proton pumping ATPases is basically the same as that of F-type ATPases, except that V-ATPases cannot synthesize ATP from the proton motive force, the reverse reaction of pumping. When pumping, ATP hydrolysis drives a 120 degree rotation of the rotor which leads to movement of three protons into the phagosome (Adachi et al. 2007).
The sodium/potassium-transporting ATPase (ATP1A:ATP1B:FXYD) is composed of three subunits - alpha (catalytic part), beta and gamma. The trimer catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane, creating the electrochemical gradient which provides energy for the active transport of various nutrients. Four human genes encode the catalytic alpha subunits, ATP1A1-4 (Kawakami et al, 1986; Shull et al, 1989; Ovchinnikov et al, 1988; Keryanov and Gardner, 2002). Defects in ATP1A2 cause alternating hemiplegia of childhood (AHC) (Swoboda et al, 2004). Another defect in ATP1A2 causes familial hemiplegic migraine type 2 (FHM2) (Vanmolkot et al, 2003). Defects in ATP1A3 are the cause of dystonia type 12 (DYT12) (de Carvalho Aguiar et al, 2004).
Three human genes encode the non-catalytic beta subunits, ATP1B1-3. The beta subunits are thought to mediate the number of sodium pumps transported to the plasma membrane (Lane et al, 1989; Ruiz et al, 1996; Malik et al, 1996). FXYD proteins belong to a family of small membrane proteins that are auxiliary gamma subunits of Na-K-ATPase. At least six members of this family, FYD1-4, 6 and 7, have been shown to regulate Na-K-ATPase activity (Geering 2006, Choudhury et al. 2007). Defects in FXYD2 are the cause of hypomagnesemia type 2 (HOMG2) (Meij et al, 2000).
Accumulation of calcium into the Golgi apparatus is mediated by sarco(endo)plasmic reticulum calcium-ATPases (SERCAs) and by secretory pathway calcium-ATPases (SPCAs). There are two human genes which encode SPCAs; ATP2C1 and ATP2C2 which encode magnesium-dependent calcium-transporting ATPase type 2C members 1 and 2 (ATP2C1 and 2) respectively (Sudbrak et al, 2000; Vanoevelen et al, 2005). Defects in ATP2C1 are the cause of Hailey-Hailey disease (HHD), an autosomal dominant disease characterized by persistent blisters and erosions of the skin (Hu et al, 2000).
The glycine receptor (GLR) is a ligand-gated ion channel. It is functional as a heteropentamer, consisting of alpha (GLRA) and beta (GLRB) subunits. With no ligand bound, the receptor complex is closed to chloride ions. Binding of the inhibitory neurotransmitter glycine (Gly) to this receptor complex increases chloride conductance into neurons and thus produces hyperpolarization (inhibition of neuronal firing) (Grenningloh et al. 1990, Nikolic et al. 1998, Handford et al. 1996).
Intracellular pools of Ca2+ serve as the source for inositol 1,4,5-trisphosphate (IP3) -induced alterations in cytoplasmic free Ca2+. In most human cells Ca2+ is stored in the lumen of the sarco/endoplastic reticulum by ATPases known as SERCAs (ATP2As). In platelets, ATP2As transport Ca2+ into the platelet dense tubular network. ATP2As are P-type ATPases, similar to the plasma membrane Na+ and Ca+-ATPases. Humans have three genes for SERCA pumps; ATP2A1-3. Studies on ATP2A1 suggest that it binds two Ca2+ ions from the cytoplasm and is subsequently phosphorylated at Asp351 before translocating Ca2+ into the SR lumen. There is a counter transport of two or possibly three protons ensuring partial charge balancing.
Acidification of the endosome does not continue further, and the endosome fuses again with the plasma membrane (Willingham et al, 1984; Harding et al, 1983).
The GABA(A)-rho receptor (GABRR) is expressed in many areas of the brain, but in contrast to other GABA(A) receptors, has especially high expression in the retina. It is functional as a homopentamer and is permeable to chloride ions when GABA binds to it (Cutting et al. 1991, Cutting et al. 1992, Bailey et al. 1990).
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Genetic variations in SLC17A3 influence the variance in serum uric acid concentrations and define the serum uric acid concentration quantitative trait locus 4 (UAQTL4; MIM:612671). Excess serum urate (hyperuricemia) can lead to the development of gout, characterized by tissue deposition of monosodium urate crystals.
CLCNKA and B (Kieferle et al. 1994) are predominantly expressed in distal nephron segments of the kidney (Takeuchi et al. 1995) and the inner ear (Estevez et al. 2001, Schlingmann et al. 2004). They are tightly associated with their essential beta subunit barttin (BSND), requiring it to be fully functional channels (Fischer et al. 2010, Scholl et al. 2006). These channels bound to BSND are essential for renal Cl- reabsorption (Waldegger & Jentsch 2000) and K+ recycling in the inner ear (Estevez et al. 2001). Defects in CLCNKA and B cause Bartter syndrome type 4B (BS4B; MIM:613090) characterized by impaired salt reabsorption and sensorineural deafness (Schlingmann et al. 2004, Nozu et al. 2008). Defects in BSND cause Bartter syndrome type 4A (BS4A aka infantile Bartter syndrome with sensorineural deafness; MIM:602522) characterized by impaired salt reabsorption in the thick ascending loop of Henle and sensorineural deafness (Birkenhager et al. 2001, Nozu et al. 2008).
A member of the intracellular Cl- channel protein family, CLIC2, has also been determined to inhibit RYR-mediated Ca2+ transport (Board et al. 2004), potentially playing a role in the homeostasis of Ca2+ release from intracellular stores. Inhibition is thought to be via reducing activation of the channels by their primary endogenous cytoplasmic ligands, ATP and Ca2+ (Dulhunty et al. 2005).
Defects in CLCN7 cause osteopetrosis autosomal recessive types 2 and 4 (OPTB2, MIM:166600 and OPTB4, MIM:611490) (Frattini et al. 2003, Pangrazio et al. 2010). Defects in OSTM1 cause osteopetrosis autosomal recessive type 5 (OPTB5, MIM:259720) (Pangrazio et al. 2006).
The human gene SLC11A2 encodes the divalent cation transporter DCT1 (NRAMP2, Natural resistance-associated macrophage protein 2). NRAMP2 resides on the apical membrane of enterocytes and mediates the uptake of ferrous iron into these cells (Tandy S et al, 2000). DCT1 can also accept a broad range of transition metal ions.
The human gene SLC40A1 encodes a metal transporter protein MTP1 (also called ferroportin or IREG1). This protein resides on the basolateral membrane of enterocytes and mediates ferrous iron efflux into the portal vein (Schimanski LM et al, 2005). MTP1 colocalizes with hephaestin (HEPH) which stablizes MTP1 and is necessary for the efflux reaction to occur (Han O and Kim EY, 2007; Chen H et al, 2009). As well as the dudenum, MTP1 is also highly expressed on macrophages (where it mediates iron efflux from the breakdown of haem) and the placenta (where it may mediate the transport of iron from maternal to foetal circulation). It is also expressed in muscle and spleen.
The human gene SLC40A1 encodes a metal transporter protein MTP1 (also called ferroportin or IREG1) (Schimanski LM et al, 2005). MTP1 colocalizes with ceruloplasmin (CP) which stablizes MTP1 and is necessary for the efflux reaction to occur (Texel SJ et al, 2008). Ceruloplasmin also catalyzes the conversion of iron from ferrous (Fe2+) to ferric form (Fe3+), therefore assisting in its transport in the plasma in association with transferrin, which can only carry iron in the ferric state. As well as on macrophages, MTP1 is also highly expressed in the duodenum, placenta (where it may mediate the transport of iron from maternal to foetal circulation), in muscle and the spleen.
Four human genes encode the catalytic alpha subunits, ATP1A1-4 (Kawakami et al, 1986; Shull et al, 1989; Ovchinnikov et al, 1988; Keryanov and Gardner, 2002). Defects in ATP1A2 cause alternating hemiplegia of childhood (AHC) (Swoboda et al, 2004). Another defect in ATP1A2 causes familial hemiplegic migraine type 2 (FHM2) (Vanmolkot et al, 2003). Defects in ATP1A3 are the cause of dystonia type 12 (DYT12) (de Carvalho Aguiar et al, 2004).
Three human genes encode the non-catalytic beta subunits, ATP1B1-3. The beta subunits are thought to mediate the number of sodium pumps transported to the plasma membrane (Lane et al, 1989; Ruiz et al, 1996; Malik et al, 1996). FXYD proteins belong to a family of small membrane proteins that are auxiliary gamma subunits of Na-K-ATPase. At least six members of this family, FYD1-4, 6 and 7, have been shown to regulate Na-K-ATPase activity (Geering 2006, Choudhury et al. 2007). Defects in FXYD2 are the cause of hypomagnesemia type 2 (HOMG2) (Meij et al, 2000).