BioPAX pathway converted from "Na+/H+ exchanger transport (at cell membrane)" in the Reactome database.LEFT-TO-RIGHTNa+/H+ exchanger transport (at cell membrane)NHE1 (SLC9A1) is present in most cells and is the most extensively characterized member of this family (Sardet C et al, 1989). NHE2-4 (SLC9A2-4) (Malakooti J et al, 1999; Brant SR et al, 1995) are expressed mainly in the kidney and GI tract. NHE5 (SLC9A5) (Baird NR et al, 1999) is highly expressed in neuronal-enriched areas of the CNS. Authored: Jassal, Bijay, 2009-06-11Reviewed: He, L, 2009-08-24Edited: Jassal, Bijay, 2009-06-11Na+sodium ionsodium(1+)SodiumReactome DB_ID: 74113extracellular regionGENE ONTOLOGYGO:0005576sodium(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-74113.3Reactomehttp://www.reactome.orgCOMPOUNDC01330additional informationMIMI:0361H+protonhydronReactome DB_ID: 70106cytosolGENE ONTOLOGYGO:0005829hydron [ChEBI:15378]hydronChEBICHEBI:15378Reactome Database ID Release 7570106Database 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=70106ReactomeR-ALL-701064Reactome 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-70106.4COMPOUNDC00080Na+sodium ionsodium(1+)SodiumReactome DB_ID: 83910Reactome 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-83910.3COMPOUNDC01330H+hydronReactome DB_ID: 351626Reactome Database ID Release 75351626Database 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=351626ReactomeR-ALL-3516264Reactome 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-351626.4COMPOUNDC00080ACTIVATIONConverted from EntitySet in ReactomeSLC9A1-5Na+/H+ exchanger proteinsReactome DB_ID: 425963NHE1SLC9A1Sodium/hydrogen exchanger 1SL9A1_HUMANReactome DB_ID: 426006plasma membraneGENE ONTOLOGYGO:0005886UniProt:P19634 SLC9A1SLC9A1APNH1NHE1FUNCTION Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction.SUBUNIT Oligomer (By similarity). Interacts with CALM1 in a calcium-dependent manner (PubMed:12809501, PubMed:30287853). Interacts with TESC (PubMed:11696366, PubMed:30287853, PubMed:12809501). Interacts (via the juxtamembrane region of the cytoplasmic C-terminal domain) with CHP1; the interaction occurs at the plasma membrane in a calcium-dependent manner (PubMed:8967452, PubMed:8901634, PubMed:11350981, PubMed:15035633, PubMed:17050540). Interacts with CHP2; the interaction occurs in a calcium-dependent manner (PubMed:12226101, PubMed:16710297, PubMed:21392185).TISSUE SPECIFICITY Kidney and intestine.PTM O-glycosylated.PTM Ubiquitinated, leading to its degradation by the proteasome. Ubiquitination is reduced by CHP1 (By similarity).MISCELLANEOUS Inhibited by amiloride and 5-amino-substituted derivatives and activated in a cooperative fashion by intracellular H(+). In quiescent cells upon growth factor stimulation, the apparent affinity for internal H(+) is increased, resulting in a persistent rise in cytoplasmic pH.SIMILARITY Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.CAUTION The region between transmembrane regions M4 and M5 and between M6 and M7 (also termed intracellular loops IL2 and IL4, respectively) seem to be localized at least in part in the membrane. The hydrophobic region H10 is proposed to be located within the membrane.CAUTION Although PubMed:12809501 report that TESC-binding results in a decrease in activity, studies with rat SLC9A1 show that TESC-binding results in the maturation and accumulation of SLC9A1 at the cell surface.CAUTION The interacting region with TESC is conflicting: Interaction with TESC has been reported via the juxtamembrane region of the cytoplasmic C-terminal domain, including residues 503-545 (PubMed:11696366, PubMed:30287853). In contrast, another publication has reported interaction with TESC via residues 633-815, the region of the cytoplasmic C-terminus more distal to the membrane (PubMed:12809501).Homo sapiensNCBI Taxonomy9606UniProtP196341EQUAL815EQUALReactome Database ID Release 75426006Database 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=426006ReactomeR-HSA-4260061Reactome 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-426006.1SLC9A2Sodium/hydrogen exchanger 2SL9A2_HUMANReactome DB_ID: 425975UniProt:Q9UBY0 SLC9A2SLC9A2NHE2FUNCTION Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Seems to play an important role in colonic sodium absorption.SUBUNIT Interacts with CHP1 and CHP2.TISSUE SPECIFICITY Expressed in skeletal muscle, colon and kidney. Lower levels in the testis, prostate, ovary, and small intestine.PTM Phosphorylated (Possible).SIMILARITY Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.CAUTION The number, localization and denomination of hydrophobic domains in the Na(+)/H(+) exchangers vary among authors.UniProtQ9UBY01EQUAL812EQUALReactome Database ID Release 75425975Database 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=425975ReactomeR-HSA-4259751Reactome 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-425975.1SLC9A3Sodium/hydrogen exchanger 3SL9A3_HUMANReactome DB_ID: 425992UniProt:P48764 SLC9A3SLC9A3NHE3FUNCTION Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient (PubMed:26358773). Plays an important role in signal transduction.SUBUNIT Binds SLC9A3R1 and SLC9A3R2. Interacts with CHP1, CHP2 and SHANK2. Interacts with PDZK1 (via C-terminal PDZ domain) (By similarity). Interacts with PDZD3 and interactions decrease in response to elevated calcium ion levels. Interacts with AHCYL1; the interaction is required for SLC9A3 activity (PubMed:18829453, PubMed:20584908).PTM Phosphorylated by PKA, which inhibits activity. Phosphorylation at Ser-663 by SGK1 is associated with increased abundance at the cell membrane.SIMILARITY Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.CAUTION The number, localization and denomination of hydrophobic domains in the Na(+)/H(+) exchangers vary among authors.UniProtP487641EQUAL834EQUALReactome Database ID Release 75425992Database 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=425992ReactomeR-HSA-4259921Reactome 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-425992.1SLC9A4Sodium/hydrogen exchanger 4SL9A4_HUMANReactome DB_ID: 425980UniProt:Q6AI14 SLC9A4SLC9A4NHE4FUNCTION Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction. May play a specialized role in the kidney in rectifying cell volume in response to extreme fluctuations of hyperosmolar-stimulated cell shrinkage. Is relatively amiloride and ethylisopropylamiloride (EIPA) insensitive. Can be activated under conditions of hyperosmolar-induced cell shrinkage in a sustained intracellular acidification-dependence manner. Activated by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS) in a sustained intracellular acidification-dependence manner. Affects potassium/proton exchange as well as sodium/proton and lithium/proton exchange. In basolateral cell membrane, participates in homeostatic control of intracellular pH, and may play a role in proton extrusion in order to achieve transepithelial HCO3(-) secretion. In apical cell membrane may be involved in mediating sodium absorption. Requires for normal levels of gastric acid secretion, secretory membrane development, parietal cell maturation and/or differentiation and at least secondarily for chief cell differentiation (By similarity).SUBUNIT Interacts with CHP1 and CHP2.PTM May be phosphorylated.SIMILARITY Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.CAUTION The number, localization and denomination of hydrophobic domains in the Na(+)/H(+) exchangers vary among authors.UniProtQ6AI141EQUAL798EQUALReactome Database ID Release 75425980Database 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=425980ReactomeR-HSA-4259801Reactome 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-425980.1SLC9A5Sodium/hydrogen exchanger 5SL9A5_HUMANReactome DB_ID: 425989UniProt:Q14940 SLC9A5SLC9A5NHE5FUNCTION Involved in pH regulation to eliminate acids generated by active metabolism or to counter adverse environmental conditions. Major proton extruding system driven by the inward sodium ion chemical gradient. Plays an important role in signal transduction (By similarity).SUBUNIT Interacts with CHP1 and CHP2 (By similarity). Interacts with ARRB2.TISSUE SPECIFICITY Expressed in brain, testis, spleen, and skeletal muscle.PTM Phosphorylated (Possible).SIMILARITY Belongs to the monovalent cation:proton antiporter 1 (CPA1) transporter (TC 2.A.36) family.CAUTION The number, localization and denomination of hydrophobic domains in the Na(+)/H(+) exchangers vary among authors.UniProtQ149401EQUAL896EQUALReactome Database ID Release 75425989Database 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=425989ReactomeR-HSA-4259891Reactome 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-425989.1Reactome Database ID Release 75425963Database 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=425963ReactomeR-HSA-4259631Reactome 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-425963.1GENE ONTOLOGYGO:0015385gene ontology term for cellular functionMIMI:0355Same Catalyst ActivityReactome Database ID Release 75425966Database 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=425966Reactome Database ID Release 75425994Database 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=425994ReactomeR-HSA-4259941Reactome 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-425994.110444453Pubmed1999Molecular cloning, tissue distribution, and functional expression of the human Na(+)/H(+) exchanger NHE2Malakooti, JDahdal, RYSchmidt, LLayden, TJDudeja, PKRamaswamy, KAm J Physiol 277:G383-909933641Pubmed1999Molecular cloning, genomic organization, and functional expression of Na+/H+ exchanger isoform 5 (NHE5) from human brainBaird, NROrlowski, JSzabó, EZZaun, HCSchultheis, PJMenon, AGShull, GEJ Biol Chem 274:4377-822536298Pubmed1989Molecular cloning, primary structure, and expression of the human growth factor-activatable Na+/H+ antiporterSardet, CFranchi, APouysségur, JacquesCell 56:271-807631746Pubmed1995Cloning, tissue distribution, and functional analysis of the human Na+/N+ exchanger isoform, NHE3Brant, SRYun, CHDonowitz, MTse, CMAm J Physiol 269:C198-206