BioPAX pathway converted from "Cation-coupled Chloride cotransporters" in the Reactome database.Cation-coupled Chloride cotransportersThe cation-chloride cotransporter family (SLC12 gene family) are membrane proteins that cotranslocate chloride (Cl-) with either Na+, K+, or both cations electroneutrally. The general topology of these proteins feature 12 transmembrane domains flanked by hydrophilic NH2 and COOH-terminal domains. They are secondary transporters and movement of these cations is determined by gradients established by primary transporters such as Na+-K+-ATPase. Cotransporters that use Na+ as the driving force move Cl- into the cell because Na+ concentration is higher in the extracellular region. Conversely, cotransporters that use K+ as the driving force move Cl- out of the cell because K+ concentration is higher inside the cell.<br><br>The SLC12 gene family contains nine members, of which seven are clearly characterized genes and two are orphans. They encode cotransporter proteins which are 1) involved in Cl- homeostasis, 2) regulate cell volume, 3) involved in transepithelial ion movement (salt reabsorption in the kidney) and 4) involved in response to neurotransmitters such as GABA. <br><br>Three different cotransporter subtypes are expressed by the seven characterized genes; one thiazide-sensitive Na+/Cl- cotransporter, two loop diuretic-sensitive Na+, K+/2Cl- cotransporters and four K+/Cl- cotransporters (Gamba G, 2005; Hebert SC et al, 2004).Authored: Jassal, Bijay, 2009-06-12Reviewed: He, L, 2009-08-24Edited: Jassal, Bijay, 2009-06-12LEFT-TO-RIGHTNa+/Cl- cotransportSLC12A3 cotransports Cl-, Na+ from extracellular region to cytosolThe SLC12A3 gene encodes for the Thiazide-sensitive sodium-chloride cotransporter (TSC). TSC mediates sodium and chloride removal from the distal convoluted tubule of the kidney (Mastroianni N et al, 1996). Defects in SLC12A3 are the cause of Gitelman syndrome (GS). GS is an autosomal recessive disorder that allows the kidneys to pass sodium, magnesium, chloride, and potassium into the urine, rather than being reabsorbed into the bloodstream (Simon et al. 1996). This cotransporter is the major target for thiazide-type diuretics, used in the treatment of hypertension, extracellular fluid overload and renal stone disease.Authored: Jassal, Bijay, 2009-06-12Reviewed: He, L, 2009-08-24Edited: Jassal, Bijay, 2009-06-12Cl-chlorideReactome DB_ID: 188972extracellular regionGENE ONTOLOGYGO:0005576chloride [ChEBI:17996]chlorideChEBICHEBI:17996Reactome Database ID Release 73188972Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188972ReactomeR-ALL-1889723Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-188972.3Reactomehttp://www.reactome.orgCOMPOUNDC00115additional informationMIMI:0361Na+sodium ionsodium(1+)SodiumReactome DB_ID: 74113sodium(1+) [ChEBI:29101]sodium(1+)ChEBICHEBI:29101Reactome Database ID Release 7374113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74113ReactomeR-ALL-741133Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74113.3COMPOUNDC01330Cl-chlorideReactome DB_ID: 352022cytosolGENE ONTOLOGYGO:0005829Reactome Database ID Release 73352022Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=352022ReactomeR-ALL-3520223Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-352022.3COMPOUNDC00115Na+sodium ionsodium(1+)SodiumReactome DB_ID: 83910Reactome Database ID Release 7383910Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=83910ReactomeR-ALL-839103Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-83910.3COMPOUNDC01330ACTIVATIONSLC12A3Solute carrier family 12 member 3S12A3_HUMANReactome DB_ID: 426147plasma membraneGENE ONTOLOGYGO:0005886UniProt:P55017 SLC12A3SLC12A3NCCTSCFUNCTION Electroneutral sodium and chloride ion cotransporter. In kidney distal convoluted tubules, key mediator of sodium and chloride reabsorption (PubMed:21613606, PubMed:22009145). Receptor for the proinflammatory cytokine IL18. Contributes to IL18-induced cytokine production, including IFNG, IL6, IL18 and CCL2. May act either independently of IL18R1, or in a complex with IL18R1 (By similarity).ACTIVITY REGULATION Activated by WNK3.SUBUNIT Interacts with KLHL3 (PubMed:22406640). Interacts with IL18R1; this interaction is increased by IL18 treatment (By similarity).TISSUE SPECIFICITY Predominantly expressed in kidney (PubMed:8812482). Not detected in normal aorta, but abundantly expressed in fatty streaks and advanced atherosclerotic lesions (at protein level) (PubMed:26099046).PTM Ubiquitinated; ubiquitination is essential for regulation of endocytosis. The BCR(KLHL3) complex was initially identified as a candidate ubiquitin ligase for SLC12A3 (PubMed:22406640). However, it was later shown that it is not the case.PTM Phosphorylated in response to IL18.MISCELLANEOUS Target of thiazide diuretics used in the treatment of high blood pressure.SIMILARITY Belongs to the SLC12A transporter family.Homo sapiensNCBI Taxonomy9606UniProtP550171EQUAL1021EQUALReactome Database ID Release 73426147Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426147ReactomeR-HSA-4261471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426147.1GENE ONTOLOGYGO:0015378gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 73426160Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426160Reactome Database ID Release 73426130Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426130ReactomeR-HSA-4261301Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426130.18812482Pubmed1996Molecular cloning, expression pattern, and chromosomal localization of the human Na-Cl thiazide-sensitive cotransporter (SLC12A3)Mastroianni, NDe Fusco, MZollo, MArrigo, GZuffardi, OBettinelli, ABallabio, ACasari, GGenomics 35:486-938528245Pubmed1996Gitelman's variant of Bartter's syndrome, inherited hypokalaemic alkalosis, is caused by mutations in the thiazide-sensitive Na-Cl cotransporterSimon, DBNelson-Williams, CBia, MJEllison, DKaret, FEMolina, AMVaara, IIwata, FCushner, HMKoolen, MGainza, FJGitleman, HJLifton, RPNat Genet 12:24-30LEFT-TO-RIGHTNa+, K+/2Cl- cotransportSLC12A1,2 cotransports Na+, K+, 2Cl- from extracellular region to cytosolTwo genes (SLC12A1 and SLC12A2) encode Na+,K+/2Cl- cotransporters (NKCC2 and NKCC1 respectively). SLC12A1 (Simon DB et al, 1996) is kidney-specific whilst SLC12A2 (Payne JA et al, 1995) is ubiquitously expressed. Two Cl- ions are electroneutrally transported into cells with a Na+ ion and a K+ ion.Authored: Jassal, Bijay, 2009-06-12Reviewed: He, L, 2009-08-24Edited: Jassal, Bijay, 2009-06-122K+Potassiumpotassium(1+)Reactome DB_ID: 74126potassium(1+) [ChEBI:29103]potassium(1+)PotassiumK+ChEBICHEBI:29103Reactome Database ID Release 7374126Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=74126ReactomeR-ALL-741263Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-74126.3COMPOUNDC002382K+Potassiumpotassium(1+)Reactome DB_ID: 29804Reactome Database ID Release 7329804Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=29804ReactomeR-ALL-298043Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-ALL-29804.3COMPOUNDC00238ACTIVATIONConverted from EntitySet in ReactomeSLC12A1,2NKCC cotransportersReactome DB_ID: 426153SLC12A1Solute carrier family 12 member 1S12A1_HUMANReactome DB_ID: 426139UniProt:Q13621 SLC12A1SLC12A1NKCC2FUNCTION Renal sodium, potassium and chloride ion cotransporter that mediates the transepithelial NaCl reabsorption in the thick ascending limb and plays an essential role in the urinary concentration and volume regulation. Electrically silent transporter system.ACTIVITY REGULATION Activated by WNK3.SUBUNIT When phosphorylated, interacts with PPP3CB.TISSUE SPECIFICITY Kidney specific.SIMILARITY Belongs to the SLC12A transporter family.UniProtQ136211EQUAL1099EQUALReactome Database ID Release 73426139Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426139ReactomeR-HSA-4261391Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426139.1SLC12A2Solute carrier family 12 member 2S12A2_HUMANReactome DB_ID: 426146UniProt:P55011 SLC12A2SLC12A2NKCC1FUNCTION Electrically silent transporter system. Mediates sodium and chloride reabsorption. Plays a vital role in the regulation of ionic balance and cell volume.ACTIVITY REGULATION Activated by WNK3.TISSUE SPECIFICITY Expressed in many tissues.SIMILARITY Belongs to the SLC12A transporter family.UniProtP550111EQUAL1212EQUALReactome Database ID Release 73426146Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426146ReactomeR-HSA-4261461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426146.1Reactome Database ID Release 73426153Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426153ReactomeR-HSA-4261531Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426153.1GENE ONTOLOGYGO:0008511Reactome Database ID Release 73426140Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426140Reactome Database ID Release 73426086Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426086ReactomeR-HSA-4260861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426086.18640224Pubmed1996Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2Simon, DBKaret, FEHamdan, JMDiPietro, ASanjad, SALifton, RPNat Genet 13:183-87629105Pubmed1995Primary structure, functional expression, and chromosomal localization of the bumetanide-sensitive Na-K-Cl cotransporter in human colonPayne, JAXu, JCHaas, MLytle, CYWard, DForbush B, 3rdJ Biol Chem 270:17977-85LEFT-TO-RIGHTK+/Cl- cotransportSLC12A4,5,6,7 cotransport K+, Cl- from cytosol to extracellular regionK+/Cl- cotransport is implicated not only in regulatory volume decrease, but also in transepithelial salt absorption, renal K+ secretion, myocardial K+ loss during ischemia and regulation of neuronal Cl- concentration. Four genes (SLC12A4-7) encode the K+/Cl- cotransporters KCC1-4 respectively. Cotransport of K+ and Cl- is electroneutral with a 1:1 stoichiometry. These cotransporters function as homomultimers or heteromultimers with other K+/Cl- cotransporters.<br>SLC12A4 encodes KCC1 (Gillen CM et al, 1996). KCC1 is ubiquitously expressed, suggesting a housekeeping role in the regulation of cell volume. SLC12A5 encodes KCC2 (Song L et al, 2002). KCC2's expression is restricted to neurons in the CNS and retina. It is thought KCC2 is important for Cl- homeostasis in neurons. SLC12A6 encodes KCC3 (Race JE et al, 1999; Mount DB et al, 1999). KCC3 is highly expressed in heart, brain, spinal cord, kidney, muscle, pancreas and placenta. Defects in SLC12A6 are a cause of agenesis of the corpus callosum with peripheral neuropathy (ACCPN) (Howard HC et al, 2002). SLC12A7 encodes KCC4 (Mount DB et al, 1999) which is widely expressed, especially in the kidney. It is thought to play a role in transepithelial transport of Cl- by the proximal tubule.Authored: Jassal, Bijay, 2009-06-12Reviewed: He, L, 2009-08-24Edited: Jassal, Bijay, 2009-06-12ACTIVATIONConverted from EntitySet in ReactomeSLC12A4,5,6,7KCC cotransportersReactome DB_ID: 426109SLC12A4Solute carrier family 12 member 4S12A4_HUMANReactome DB_ID: 426167UniProt:Q9UP95 SLC12A4SLC12A4KCC1FUNCTION Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May contribute to cell volume homeostasis in single cells. May be involved in the regulation of basolateral Cl(-) exit in NaCl absorbing epithelia (By similarity). Isoform 4 has no transport activity.ACTIVITY REGULATION Inhibited by WNK3.SUBUNIT Homomultimer and heteromultimer with other K-Cl cotransporters.TISSUE SPECIFICITY Ubiquitous. Levels are much higher in erythrocytes from patients with Hb SC and Hb SS compared to normal AA erythrocytes. This may contribute to red blood cell dehydration and to the manifestation of sickle cell disease by increasing the intracellular concentration of HbS. Isoform 1 was not detected in circulating reticulocytes.PTM N-glycosylated.SIMILARITY Belongs to the SLC12A transporter family.UniProtQ9UP951EQUAL1085EQUALReactome Database ID Release 73426167Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426167ReactomeR-HSA-4261671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426167.1SLC12A5Solute carrier family 12 member 5S12A5_HUMANReactome DB_ID: 426150UniProt:Q9H2X9 SLC12A5SLC12A5KCC2KIAA1176FUNCTION Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis. As major extruder of intracellular chloride, it establishes the low neuronal Cl(-) levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition (By similarity). Involved in the regulation of dendritic spine formation and maturation (PubMed:24668262).ACTIVITY REGULATION Inhibited by WNK3.SUBUNIT Homomultimer and heteromultimer with other K-Cl cotransporters. Interacts with AP2A1 (By similarity).TISSUE SPECIFICITY Brain specific. Detected in neuronal cells.MISCELLANEOUS Inhibited by furosemide and bumetanide.SIMILARITY Belongs to the SLC12A transporter family.UniProtQ9H2X91EQUAL1139EQUALReactome Database ID Release 73426150Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426150ReactomeR-HSA-4261501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426150.1SLC12A6Solute carrier family 12 member 6S12A6_HUMANReactome DB_ID: 426107UniProt:Q9UHW9 SLC12A6SLC12A6KCC3FUNCTION Mediates electroneutral potassium-chloride cotransport. May be activated by cell swelling. May contribute to cell volume homeostasis in single cells.ACTIVITY REGULATION Activated by N-ethylmaleimide (NEM). Inhibited by DIOA, bumetanide and furosemide. Inhibited by WNK3.SUBUNIT Homomultimer and heteromultimer with other K-Cl cotransporters.TISSUE SPECIFICITY Highly expressed in heart, brain and kidney. Detected at lower levels in skeletal muscle, placenta, lung and pancreas. Detected in umbilical vein endothelial cells. Isoform 2 is more abundant in kidney. Isoform 5 is testis specific. Expressed in the proximal tubule of the kidney (at protein level).INDUCTION Up-regulated by VEGF. Down-regulated by TNF.PTM N-glycosylated.SIMILARITY Belongs to the SLC12A transporter family.UniProtQ9UHW91EQUAL1150EQUALReactome Database ID Release 73426107Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426107ReactomeR-HSA-4261071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426107.1SLC12A7Solute carrier family 12 member 7S12A7_HUMANReactome DB_ID: 426164UniProt:Q9Y666 SLC12A7SLC12A7KCC4FUNCTION Mediates electroneutral potassium-chloride cotransport when activated by cell swelling. May mediate K(+) uptake into Deiters' cells in the cochlea and contribute to K(+) recycling in the inner ear. Important for the survival of cochlear outer and inner hair cells and the maintenance of the organ of Corti. May be required for basolateral Cl(-) extrusion in the kidney and contribute to renal acidification (By similarity).ACTIVITY REGULATION Activated by N-ethylmaleimide (NEM). Inhibited by furosemide, DIDS and bumetanide. The inhibition is much stronger in the presence of 50 mM K(+) in the uptake medium. Inhibited by DIOA. Inhibited by WNK3.SUBUNIT Homomultimer and heteromultimer with other K-Cl cotransporters.TISSUE SPECIFICITY Detected in muscle, brain, lung, heart and kidney.SIMILARITY Belongs to the SLC12A transporter family.UniProtQ9Y6661EQUAL1083EQUALReactome Database ID Release 73426164Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426164ReactomeR-HSA-4261641Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426164.1Reactome Database ID Release 73426109Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426109ReactomeR-HSA-4261091Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426109.1GENE ONTOLOGYGO:0015379Reactome Database ID Release 73426138Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426138Reactome Database ID Release 73426155Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426155ReactomeR-HSA-4261551Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426155.112106695Pubmed2002Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporterSong, LMercado, AVázquez, NXie, QDesai, RGeorge AL, JrGamba, GMount, DBBrain Res Mol Brain Res 103:91-10510600773Pubmed1999Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporterRace, JEMakhlouf, FNLogue, PJWilson, FHDunham, PBHoltzman, EJAm J Physiol 277:C1210-910347194Pubmed1999Cloning and characterization of KCC3 and KCC4, new members of the cation-chloride cotransporter gene familyMount, DBMercado, ASong, LXu, JGeorge AL, JrDelpire, EGamba, GJ Biol Chem 274:16355-628663127Pubmed1996Molecular cloning and functional expression of the K-Cl cotransporter from rabbit, rat, and human. A new member of the cation-chloride cotransporter familyGillen, CMBrill, SPayne, JAForbush B, 3rdJ Biol Chem 271:16237-4412368912Pubmed2002The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosumHoward, HCMount, DBRochefort, DByun, NDupré, NLu, JFan, XSong, LRivière, JBPrévost, CHorst, JSimonati, ALemcke, BWelch, REngland, RZhan, FQMercado, ASiesser, WBGeorge AL, JrMcDonald, MPBouchard, JPMathieu, JDelpire, ERouleau, Guy ANat Genet 32:384-92Reactome Database ID Release 73426117Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=426117ReactomeR-HSA-4261171Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-426117.115788703Pubmed2005Molecular physiology and pathophysiology of electroneutral cation-chloride cotransportersGamba, GPhysiol Rev 85:423-9312739168Pubmed2004Molecular physiology of cation-coupled Cl- cotransport: the SLC12 familyHebert, SCMount, DBGamba, GPflugers Arch 447:580-93