Ion channels mediate the flow of ions across the plasma membrane of cells. They are integral membrane proteins, typically a multimer of proteins, which, when arranged in the membrane, create a pore for the flow of ions. There are different types of ion channels. P-type ATPases undergo conformational changes to translocate ions. Ligand-gated ion channels operate like a gate, opened or closed by a chemical signal. Voltage-gated ion channels are activated by changes in electrical potential difference at the membrane (Purves, 2001; Kuhlbrandt, 2004).
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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
Schatzmann HJ.; ''ATP-dependent Ca++-extrusion from human red cells.''; 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
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
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
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Lane LK, Shull MM, Whitmer KR, Lingrel JB.; ''Characterization of two genes for the human Na,K-ATPase beta subunit.''; PubMedEurope PMCScholia
Tian Y, Schreiber R, Kunzelmann K.; ''Anoctamins are a family of Ca2+-activated Cl- channels.''; 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
Fischer M, Janssen AG, Fahlke C.; ''Barttin activates ClC-K channel function by modulating gating.''; PubMedEurope PMCScholia
Toda M, Tulic MK, Levitt RC, Hamid Q.; ''A calcium-activated chloride channel (HCLCA1) is strongly related to IL-9 expression and mucus production in bronchial epithelium of patients with asthma.''; PubMedEurope PMCScholia
Hoshino M, Morita S, Iwashita H, Sagiya Y, Nagi T, Nakanishi A, Ashida Y, Nishimura O, Fujisawa Y, Fujino M.; ''Increased expression of the human Ca2+-activated Cl- channel 1 (CaCC1) gene in the asthmatic airway.''; PubMedEurope PMCScholia
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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
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Kwasnicka-Crawford DA, Carson AR, Roberts W, Summers AM, Rehnström K, Järvelä I, Scherer SW.; ''Characterization of a novel cation transporter ATPase gene (ATP13A4) interrupted by 3q25-q29 inversion in an individual with language delay.''; 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
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
Franceschini S, Ilari A, Verzili D, Zamparelli C, Antaramian A, Rueda A, Valdivia HH, Chiancone E, Colotti G.; ''Molecular basis for the impaired function of the natural F112L sorcin mutant: X-ray crystal structure, calcium affinity, and interaction with annexin VII and the ryanodine receptor.''; PubMedEurope PMCScholia
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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
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
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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
Sun H, Tsunenari T, Yau KW, Nathans J.; ''The vitelliform macular dystrophy protein defines a new family of chloride channels.''; PubMedEurope PMCScholia
Li J, Ji C, Chen J, Yang Z, Wang Y, Fei X, Zheng M, Gu X, Wen G, Xie Y, Mao Y.; ''Identification and characterization of a novel Cut family cDNA that encodes human copper transporter protein CutC.''; PubMedEurope PMCScholia
Waldegger S, Jentsch TJ.; ''Functional and structural analysis of ClC-K chloride channels involved in renal disease.''; 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
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
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
Paulusma CC, Oude Elferink RP.; ''The type 4 subfamily of P-type ATPases, putative aminophospholipid translocases with a role in human disease.''; 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
Prawitt D, Monteilh-Zoller MK, Brixel L, Spangenberg C, Zabel B, Fleig A, Penner R.; ''TRPM5 is a transient Ca2+-activated cation channel responding to rapid changes in [Ca2+]i.''; 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
Kühlbrandt W.; ''Biology, structure and mechanism of P-type ATPases.''; PubMedEurope PMCScholia
Spamer C, Heilmann C, Gerok W.; ''Ca2+-activated ATPase in microsomes from human liver.''; PubMedEurope PMCScholia
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Marx SO, Reiken S, Hisamatsu Y, Jayaraman T, Burkhoff D, Rosemblit N, Marks AR.; ''PKA phosphorylation dissociates FKBP12.6 from the calcium release channel (ryanodine receptor): defective regulation in failing hearts.''; 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
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Wu LJ, Sweet TB, Clapham DE.; ''International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP ion channel family.''; PubMedEurope PMCScholia
Kamada F, Suzuki Y, Shao C, Tamari M, Hasegawa K, Hirota T, Shimizu M, Takahashi N, Mao XQ, Doi S, Fujiwara H, Miyatake A, Fujita K, Chiba Y, Aoki Y, Kure S, Tamura G, Shirakawa T, Matsubara Y.; ''Association of the hCLCA1 gene with childhood and adult asthma.''; PubMedEurope PMCScholia
Schmidt K, Wolfe DM, Stiller B, Pearce DA.; ''Cd2+, Mn2+, Ni2+ and Se2+ toxicity to Saccharomyces cerevisiae lacking YPK9p the orthologue of human ATP13A2.''; PubMedEurope PMCScholia
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Fujii J, Willard HF, MacLennan DH.; ''Characterization and localization to human chromosome 1 of human fast-twitch skeletal muscle calsequestrin gene.''; PubMedEurope PMCScholia
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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
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
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
Ruiz A, Bhat SP, Bok D.; ''Expression and synthesis of the Na,K-ATPase beta 2 subunit in human retinal pigment epithelium.''; 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
Ishibashi K, Marumo F.; ''Molecular cloning of a DEG/ENaC sodium channel cDNA from human testis.''; 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
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
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
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
Qin A, Cheng TS, Lin Z, Pavlos NJ, Jiang Q, Xu J, Dai KR, Zheng MH.; ''Versatile roles of V-ATPases accessory subunit Ac45 in osteoclast formation and function.''; 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
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
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
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
Launay P, Fleig A, Perraud AL, Scharenberg AM, Penner R, Kinet JP.; ''TRPM4 is a Ca2+-activated nonselective cation channel mediating cell membrane depolarization.''; 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
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
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
Toyofuku T, Curotto Kurzydlowski K, Narayanan N, MacLennan DH.; ''Identification of Ser38 as the site in cardiac sarcoplasmic reticulum Ca(2+)-ATPase that is phosphorylated by Ca2+/calmodulin-dependent protein kinase.''; 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
Keryanov S, Gardner KL.; ''Physical mapping and characterization of the human Na,K-ATPase isoform, ATP1A4.''; 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
Calafato S, Swain S, Hughes S, Kille P, Stürzenbaum SR.; ''Knock down of Caenorhabditis elegans cutc-1 exacerbates the sensitivity toward high levels of copper.''; 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
Suzuki M, Mizuno A.; ''A novel human Cl(-) channel family related to Drosophila flightless locus.''; PubMedEurope PMCScholia
Li Y, Du J, Zhang P, Ding J.; ''Crystal structure of human copper homeostasis protein CutC reveals a potential copper-binding site.''; 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
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
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
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).
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).
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).
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).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
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, Lanner et al. 2010). The function of RYRs are controlled by peptidyl-prolyl cis-trans isomerase (FKBP1B), 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 polymerise (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 (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). Protein kinase A (PKA) phosphorylation of RYR2 dissociates FKBP1B and results in defective channel function (Marx et al. 2000). The penta-EF hand protein sorcin (SRI) can modulate Ca2+-induced calcium-release in the heart via the interaction with several Ca2+ channels such as RYRs. A natural ligand, F112L, impairs this modulating activity (Franceschini et al. 2008). Calmodulin (CALM1) is considered a gatekeeper of RYR2. CALM1 acts directly by binding to RYR2 at residues 3583–3603, inhibiting RYR2 both at physiological and higher, pathological Ca2+ concentrations (Smith et al. 1989, Ono et al. 2010).
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 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).
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.
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).
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.
Most members of the TRP channel family are permeable to Ca2+. Although TRPM4 and 5 can be activated by increased levels of intracellular Ca2+, they are impermeable to it. Instead, they are monovalent-selective with highest affinity for Na+ transport, of which leads to depolarization of the membrane (Launay et al. 2002, Prawitt et al. 2003). They play a central role in cardiomyocytes, neurons, endocrine pancreas cells, kidney epithelial cells and cochlea hair cells.
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.
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. Sarcolipin (SLN) can reversibly inhibit the activity of ATP2A1 by decreasing the apparent affinity of the ATPase for Ca2+ (Gorski et al. 2013) whereas activated Ca2+/CaM-dependent protein kinase II (CAMK2) and sorcin (SRI) can both stimulate ATP2A1-3 activity (Toyofuku et al. 1994, Matsumoto et al. 2005).
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. Sarcolipin (SLN) can reversibly inhibit the activity of ATP2A1 by decreasing the apparent affinity of the ATPase for Ca2+ (Gorski et al. 2013) whereas activated Ca2+/CaM-dependent protein kinase II (CAMK2) and sorcin (SRI) can both stimulate ATP2A1-3 activity (Toyofuku et al. 1994, Matsumoto et al. 2005).
Probable cation-transporting ATPases 13A4 and 13A5 (ATP13A4, 5) belong to the P5 subfamily of P-tpre ATPases. This subfamily is the most poorly understood in terms of chracterisation and function. The yeast orthologue YPK9 (aka Yor291w) shows toxicity when deleted from yeast cells, suggesting a role in sequestration of divalent heavy metal ions (Schmidt et al. 2009). The ATP13A4 gene may be disrupted by a 3q25-q29 inversion of the long arm of chromosome 3, which may result in a specific language impairment (SLI) (Kwasnicka-Crawford et al. 2005).
Vacuolar-type H+-ATPases (V-ATPases) are proton pumps that acidify intracellular cargos and deliver protons across the plasma membrane of many specialised cells. V-type proton ATPase subunit S1 (ATP6AP1) is thought to function as an accessory subunit of the V0 subcomplex of V-ATPase, facilitating acidification (Supek et al. 1994). Experiments with the mouse orthologue reveals a role for Atp6ap1 in osteoclast formation and function (Qin et al. 2011).
Calcium-activated chloride channel regulators 1,2,3P and 4 (CLCA1,2,3P and 4), originally named as CLCAs based on the observation that overexpression of them all induced chloride current in response to cytosolic calcium flux. More recent evidence points to them being secreted proteins (Gibson et al. 2005) and being responsible for chloride channel modulation rather that forming chloride channels per se (Hamann et al. 2009). CLCA1 has been found to be overexpressed in aiways of patients suffering from asthma and chronic obstructive pulmonary disease (Hoshino et al. 2002, Toda et al. 2002, Kamada et al. 2004). All CLCAs contain a consensus cleavage motif which is recognised by an internal zincin metalloprotease domain within the N terminus. Self-proteolysis within the secretory pathway yields N- and C-terminal fragments, a step critical for CLCA activation of calcium-activated chloride channels (CaCCs) mediated through the N-terminal fragment (Yurtsever et al. 2012).
A potential regulator of human copper metabolism has recently been described. Copper homeostasis protein cutC homolog (CutC) is a highly conserved cytosolic copper binding protein (Li et al. 2005, Li et al. 2010). Its function in human copper metabolism remains unclear but in C. elegans, the orthologous cutc1 protein down-regulation increases sensitivity to high levels of copper (Calafato et al. 2008).
Manganese-transporting ATPase 13A1 (ATP13A1) mediates the transport of manganese (Mn2+) into the endoplasmic reticulum. ATPase activity is required for cellular manganese homeostasis (Cohen et al. 2013).
The probable cation-transporting ATPase 13A2 (ATP13A2) is thought to play a role in intracellular cation homeostasis and the maintenance of neuronal integrity (Ramonet et al. 2012). Defects in ATP13A2 can cause Kufor-Rakeb syndrome (KRS; MIM:606693), a juvenile-onset Levodopa-responsive parkinsonism (Lai et al. 2012).
Stomatin (STOM) and Stomatin-like protein 3 (STOML3) are accessory proteins for the ASIC channels (Zeng et al. 2014). STOML3 and stomatin are expressed by primary sensory neurons of the dorsal root ganglia (DRG) (Mannsfeldt et al. 1999, Wetzel et al. 2007) and regulate mechanoreceptor sensitivity in mice (Wetzel et al. 2007, Martinez-Saldago et al. 2007). STOML3 and to a lesser extent STOM can modulate the gating of ASICs (Price et al. 2004, Wetzel et al. 2007). STOML3 can bind ASIC1a, 1b, 2a, 2b, 3 and 4 (Lapatsina et al. 2012) . The function of STOML3 may be to prime the transduction complex for insertion into the plasma membrane (Lapatsina et al. 2012). Alternatively, STOML3 may control membrane mechanics by binding cholesterol to tune the sensitivity of mechano-gated channels(Qi et al. 2015).
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).
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 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 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). ATP1A1-4 and ATP1B1-4 play a minor role during phase 2, since they begin to restore ion concentrations. The high concentration of intracellular calcium starts contraction of those cells, which is sustained in the plateau phase.
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 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).
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).
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tetramer:FKBP1B tetramer:CASQ
polymer:TRDN:junctinAnnotated Interactions
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).
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). Protein kinase A (PKA) phosphorylation of RYR2 dissociates FKBP1B and results in defective channel function (Marx et al. 2000). The penta-EF hand protein sorcin (SRI) can modulate Ca2+-induced calcium-release in the heart via the interaction with several Ca2+ channels such as RYRs. A natural ligand, F112L, impairs this modulating activity (Franceschini et al. 2008). Calmodulin (CALM1) is considered a gatekeeper of RYR2. CALM1 acts directly by binding to RYR2 at residues 3583–3603, inhibiting RYR2 both at physiological and higher, pathological Ca2+ concentrations (Smith et al. 1989, Ono 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.
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). ATP1A1-4 and ATP1B1-4 play a minor role during phase 2, since they begin to restore ion concentrations. The high concentration of intracellular calcium starts contraction of those cells, which is sustained in the plateau phase.
tetramer:FKBP1B tetramer:CASQ
polymer:TRDN:junctin