BioPAX pathway converted from "Cation-coupled Chloride cotransporters" in the Reactome database.Cation-coupled Chloride cotransportersThis event has been computationally inferred from an event that has been demonstrated in another species.The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>LEFT-TO-RIGHTNa+, K+/2Cl- cotransportSLC12A1,2 cotransports Na+, K+, 2Cl- from extracellular region to cytosolThis event has been computationally inferred from an event that has been demonstrated in another species.The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>K+Potassiumpotassium(1+)Reactome DB_ID: 74126extracellular regionGENE ONTOLOGYGO:0005576potassium(1+) [ChEBI:29103]potassium(1+)PotassiumK+ChEBICHEBI:29103Reactome Database ID Release 7574126Database 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-74126.3Reactomehttp://www.reactome.orgCOMPOUNDC00238additional informationMIMI:0361Na+sodium ionsodium(1+)SodiumReactome DB_ID: 74113sodium(1+) [ChEBI:29101]sodium(1+)ChEBICHEBI:29101Reactome Database ID Release 7574113Database 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: 188972chloride [ChEBI:17996]chlorideChEBICHEBI:17996Reactome Database ID Release 75188972Database 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-188972.3COMPOUNDC001152Na+sodium ionsodium(1+)SodiumReactome DB_ID: 83910cytosolGENE ONTOLOGYGO:0005829Reactome Database ID Release 7583910Database 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-83910.3COMPOUNDC01330Cl-chlorideReactome DB_ID: 352022Reactome Database ID Release 75352022Database 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-352022.3COMPOUNDC001152K+Potassiumpotassium(1+)Reactome DB_ID: 29804Reactome Database ID Release 7529804Database 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: 10435590E1BTK6SLC12A1SLC12A1Reactome DB_ID: 10435584plasma membraneGENE ONTOLOGYGO:0005886UniProt:E1BTK6SLC12A1Gallus gallusNCBI Taxonomy9031UniProtE1BTK61EQUAL1099EQUALReactome Database ID Release 7510435584Database 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=10435584ReactomeR-GGA-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-GGA-426139.1F1NR57SLC12A2Reactome DB_ID: 10435588UniProt:F1NR57UniProtF1NR571EQUAL1212EQUALReactome Database ID Release 7510435588Database 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=10435588ReactomeR-GGA-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-GGA-426146.1Reactome Database ID Release 7510435590Database 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=10435590ReactomeR-GGA-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-GGA-426153.1GENE ONTOLOGYGO:0008511gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 7510435591Database 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=10435591Reactome Database ID Release 7510435593Database 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=10435593ReactomeR-GGA-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-GGA-426086.1Two 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.7629105Pubmed1995Primary 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 270:17977-858640224Pubmed1996Bartter's syndrome, hypokalaemic alkalosis with hypercalciuria, is caused by mutations in the Na-K-2Cl cotransporter NKCC2Simon, DBKaret, FEHamdan, JMDiPietro, ASanjad, SALifton, RPNat Genet 13:183-8inferred from electronic annotationEVIDENCE CODEECO:0000203LEFT-TO-RIGHTK+/Cl- cotransportSLC12A4,5,6,7 cotransport K+, Cl- from cytosol to extracellular regionThis event has been computationally inferred from an event that has been demonstrated in another species.The inference is based on the homology mapping from PANTHER. Briefly, reactions for which all involved PhysicalEntities (in input, output and catalyst) have a mapped orthologue/paralogue (for complexes at least 75% of components must have a mapping) are inferred to the other species. High level events are also inferred for these events to allow for easier navigation.<a href='/electronic_inference_compara.html' target = 'NEW'>More details and caveats of the event inference in Reactome.</a> For details on PANTHER see also: <a href='http://www.pantherdb.org/about.jsp' target='NEW'>http://www.pantherdb.org/about.jsp</a>ACTIVATIONConverted from EntitySet in ReactomeSLC12A4,5,6,7KCC cotransportersReactome DB_ID: 10435607SLC12A4SLC12A4A0A3Q2U2M5Reactome DB_ID: 10435597UniProt:A0A3Q2U2M5SLC12A4UniProtA0A3Q2U2M51EQUAL1085EQUALReactome Database ID Release 7510435597Database 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=10435597ReactomeR-GGA-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-GGA-426167.1SLC12A5SLC12A5A0A1D5NV36Reactome DB_ID: 10435601UniProt:A0A1D5NV36SLC12A5UniProtA0A1D5NV361EQUAL1139EQUALReactome Database ID Release 7510435601Database 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=10435601ReactomeR-GGA-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-GGA-426150.1SLC12A7SLC12A7A0A1D5P9V5Reactome DB_ID: 10435605UniProt:A0A1D5P9V5SLC12A7UniProtA0A1D5P9V51EQUAL1083EQUALReactome Database ID Release 7510435605Database 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=10435605ReactomeR-GGA-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-GGA-426164.1Reactome Database ID Release 7510435607Database 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=10435607ReactomeR-GGA-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-GGA-426109.1GENE ONTOLOGYGO:0015379Reactome Database ID Release 7510435608Database 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=10435608Reactome Database ID Release 7510435610Database 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=10435610ReactomeR-GGA-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-GGA-426155.1K+/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. 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.8663127Pubmed1996Molecular 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 271:16237-4410347194Pubmed1999Cloning 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 274:16355-6210600773Pubmed1999Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporterRace, JEMakhlouf, FNLogue, PJWilson, FHDunham, PBHoltzman, EJAm J Physiol 277:C1210-912106695Pubmed2002Molecular, 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 103:91-10512368912Pubmed2002The 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 7510489364Database 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=10489364ReactomeR-GGA-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-GGA-426117.1The 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. 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. 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).15788703Pubmed2005Molecular 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