TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*2.A.19.1.1









Ca2+:H+ antiporter (also catalyzes Na+:H+ and K+:H+ antiport in processes that have been shown to be physiologically important under certain conditions) (Ivey et al., 1993; Radchenko et al., 2006)
Bacteria
Proteobacteria
ChaA of E. coli
*2.A.19.2.1









Ca2+:H+ antiporter
Bacteria
Cyanobacteria
Ca2+:H+ antiporter of Synechocystis
*2.A.19.2.2









Vacuolar [Mn2+ or Ca2+]:H+ antiporter, Hum1 (Mn2+ resistance (Mnr1)) protein. Vcx1 has 11 probable TMSs with the N-terminus inside (Segarra and Thomas, 2008).  The 3-d structure has been determined at 2.3 Å resolution for the cytosolic facing, substrate bound form, favoring the alternating access mechanism of transport (Waight et al. 2013).

Eukaryota
Fungi
Hum1 (Mnr1) of Saccharomyces cerevisiae
*2.A.19.2.3









High affinity vacuolar (tonoplast) Ca2+:H+ antiporter (also exports Cd2+ and Zn2+; Shigaki et al., 2005) expressed in leaves (Cheng et al., 2005). (Determines sensitivity to abscisic acid and sugar during germination and tolerance to ethylene during early seedling development (Zhao et al., 2008))
Eukaryota
Viridiplantae
Cax1 of Arabidopsis thaliana
*2.A.19.2.4









Low affinity Ca2+:H+/heavy metal cation (e.g., Mn2+, Mg2+, Cd2+, Ca2+):H+ antiporter, Cax2

Eukaryota
Viridiplantae
Cax2 of Arabidopsis thaliana
*2.A.19.2.5









High affinity vacuolar (tonoplast) Ca2+:H+ antiporter (also exports Cd2+ and Zn2+; Shigaki et al., 2005) highly expressed in roots (Cheng et al., 2005) (exhibits phenotypes characteristic of CAX1, but also determines sensitivities to salt, lithium and low pH (Zhao et al., 2008)
Eukaryota
Viridiplantae
Cax3 of Arabidopsis thaliana (Q93Z81)
*2.A.19.2.6









Algae Ca2+: H+ and Na+:H+ exchanger, CAX1 (mediates stress responses to high Ca2+, Na+ and Co2+).

Eukaryota
Viridiplantae
CAX1 of Chlamydomonas reinhardtii (B6ZCF4)
*2.A.19.2.7









Ca2+/H+ antiporter, YfkE (Fujisawa et al., 2009).
Bacteria
Firmicutes
YfkE of Bacillus subtilis (O34840)
*2.A.19.2.8









The vacuolar Ca2+:H+ exchanger, CAX (Bowman et al., 2011).

Eukaryota
Fungi
CAX of Neurospora crassa (O59940)
*2.A.19.2.9









Vacuolar cation:proton exchanger, Cax4 (transports Cd2+>Zn2+>Ca2+>Mn2+) (Cheng et al., 2002Mei et al., 2009).  The rice orthologue, Cax4, may transport Ca2+, Mn2+ and Cu2+, and functions in salt stress (Yamada et al. 2014).

Eukaryota
Viridiplantae
Cax4 of Arabidopsis thaliana (Q945S5)
*2.A.19.2.10









Vacuolar cation/proton exchanger 1a (Ca(2+)/H(+) exchanger 1a) (OsCAX1a)
Eukaryota
Viridiplantae
CAX1a of Oryza sativa subsp. japonica
*2.A.19.2.11









The Ca2+:H+ antiporter, YfkE; homotrimer with subunit size of 451 aas.  The 3-d x-ray strcuture is known to 3.1 Å resolution (Wu et al. 2013).  The conformational transition is triggered by the rotation of the kink angles of transmembrane helices 2 and 7 and is mediated by large conformational changes in their adjacent transmembrane helices 1 and 6.  The inward facing conformation contrasts with the outward facing conformation demonstrated for NCX_Mj (TC# 2.A.19.5.3).  The inward facing conformation has a "hydrophobic seal" that closes the external exit.

Bacteria
Firmicutes
YfkE of Bacillus subtilis
*2.A.19.3.1









The 10 TMS cardiac Ca2+:3 Na+ antiporter, NCX1 (Ren and Philipson 2013).  The Ca2+ sensor (residues 371-508) binds cytoplasmic Ca2+ allosterically to activate exchange activity) (Nicoll et al., 2006; Ren et al., 2006) NCX1 forms homodimers (Ren et al., 2008). It is present in mitochondria where it catalyzes Ca2+ efflux. TMS packing has been analyzed by Ren et al. (2010). Cytoplasmic Ca2+ regulates the dimeric NCX by binding to two adjacent Ca2+-binding domains (CBD1 and CBD2) located in the large intracellular loop between transmembrane segments 5 and 6. John et al. (2011) showed that Ca2+decreases the distance between the cytoplasmic loops of NCX pairs, thereby activating transport.  Ser110 in TMS2 plays a role in both Na+ and Ca2+ transport (Ottolia and Philipson 2013).

Eukaryota
Metazoa
Ca2+ regulated Ca2+:Na+ antiporter (NCX1) of Bos taurus
*2.A.19.3.2









Probable Ca2+:3Na+ antiporter, Calx (contains two repeat motifs Calx-α and Calxβ, between the two transmembrane domains, as is true of many Ca2+:Na+ antiporters (Schwarz and Benzer, 1997). CALX activity is inhibited by Ca2+ interaction within its two intracellular Ca2+ regulatory domains CBD1 and CBD2. The Ca2+ inhibition of CALX is achieved by interdomain conformational changes induced by Ca2+ binding at CBD1 (Wu et al., 2011).

Eukaryota
Metazoa
Calx of Drosophila melanogaster
(O18367)
*2.A.19.3.3









Plasma membrane sodium:calcium exchanger, NCX3, NAC3 or SLC8A3, controlling Ca2+ homeostasis. Extrudes 1 Ca2+ for 3 extracellular Na+ ions.  Potent inhibitors have been identified (Secondo et al. 2015). One such inhibitor of NCX transporters, ORM-10962, exhibits high efficacy and selectivity.  Selective NCX inhibition can exert positive as well as negative inotropic effects, depending on the actual operation mode of the NCX (Kohajda et al. 2016).

Eukaryota
Metazoa
SLC8A3 of Homo sapiens
*2.A.19.3.4









Sodium/calcium exchanger 1 (Na+/Ca2+-exchange protein 1).  The cardiac isoform, CAX1.1, like the archaeal homologues for which high resolution 3-d structures are available (TC#s 2.A.19.5.3 and 2.A.19.8.2), have two aqueous ion permeation channels with cavities that can face the cytoplasm or the external medium (John et al. 2013). It exchanges one Ca2+ ion against three to four Na+ ions, and thereby contributes to the regulation of cytoplasmic Ca2+ levels and Ca2+-dependent cellular processes (Komuro et al. 1992; , Van Eylen et al. 2001; Kofuji et al. 1992). It also contributes to Ca2+ transport during excitation-contraction coupling in muscle. In a first phase, voltage-gated channels mediate the rapid increase of cytoplasmic Ca2+ levels due to release of Ca2+ stores from the endoplasmic reticulum. SLC8A1 mediates the export of Ca2+ from the cell during the next phase, so that cytoplasmic Ca2+ levels rapidly return to baseline. It is also required for normal embryonic heart development and the onset of heart contractions. Both NCX1 and NCX2 play important roles in the motility of the gastric fundus, ileum and distal colon (Nishiyama et al. 2016). An amphipathic α-helix in the NCX1 large intracellular loop controls NCX1 palmitoylation. Thus, NCX1 palmitoylation is governed by a distal secondary structure element rather than by local primary sequence (Plain et al. 2017).

Eukaryota
Metazoa
SLC8A1 of Homo sapiens
*2.A.19.3.5









Sodium/calcium exchanger 2 (Na+/Ca2+-exchange protein 2; NCX2; SLC8A2) of 921 aas and 11 TMSs.  Functional inhibition of NCX2 initially causes natriuresis, and further inhibition produces hypercalciuria, suggesting that the functional significance of NCX2 lies in Na+ and Ca+ reabsorption in the kidney (Gotoh et al. 2015).  However NCX1-3 are present in the brain where they influence stroke theraputic strategies in a NCX subtype-specific fashion (Shenoda 2015). NCX1 and NCX2 play important roles in the motility of the gastric fundus, ileum and distal colon, but only NCX2 plays a role in the development of diarrhea (Nishiyama et al. 2016).

Eukaryota
Metazoa
SLC8A2 of Homo sapiens
*2.A.19.3.6









Full length G-protein coupled receptor 98 (GPR98); Also called Monogenic audiogenic seizure susceptibility protein 1 homologue; Usher syndrome type-2C protein; Very large G-protein coupled receptor 1 (VLGR1).  Plays a role in CNS development; exists as multiple processed isoforms.

 

Eukaryota
Metazoa
GPR98 of Homo sapiens
*2.A.19.4.1









Rod photoreceptor Ca2+ + K+:4 Na+ antiporter, NCKX1
Eukaryota
Metazoa
Ca2+ + K+:Na+ antiporter (NCKX1) of Bos taurus
*2.A.19.4.2









The major neuronal Ca2+ + K+:4 Na+ antiporter, NCKX2
Eukaryota
Metazoa
NCKX2 of Rattus norvegicus
*2.A.19.4.3









The sea urchin spermatozoan flagellar K+-dependent Ca2+:Na+ antiporter SuNCKX (Ca2+ + K+:4 Na+ antiporter)
Eukaryota
Metazoa
SuNCKX of Strongylocentrotus purpuratus
*2.A.19.4.4









K+-dependent Na+/Ca2+ antiporter, NCKX6 (Cai and Lytton, 2004). CCKX6 (NCLX) is an essential component of the mitochondrial Na+/Ca2+ exchanger (Palty et al., 2010; Drago et al., 2011).  It mediates mitochondrial Ca2+ extrusion (De Marchi et al. 2014).

Eukaryota
Metazoa
SLC24A6 of Homo sapiens
*2.A.19.4.5









The K+-dependent Na+/Ca2+ exchanger, MCKX4 (has 40x higher affinity for K+ than NCKX2 due to a threonine to alanine substitution at position 551 in NCKX2 (Visser et al., 2007)). NCKX4 is highly expressed and regulates Ca2+ transport in ameloblasts during amelogenesis (the formation of tooth enamel). In fact, MCKX4 is critical for enamel maturation (Wang et al. 2014). Residues involved in Na+ binding have been identified (Altimimi et al. 2010).

Eukaryota
Metazoa
SLC24A4 of Homo sapiens
*2.A.19.4.6









Trans-Golgi network K+-dependent Na+/Ca2+ antiporter SLC24A5 (NCKX5) (regulates melanogenesis; determines skin color variation) (Ginger et al., 2008).

Eukaryota
Metazoa
SLC24A5 of Homo sapiens
*2.A.19.4.7









The endomembrane Ca2+:cation exchanger (CCX, CAX9 or CCX3); transports H+, Na+, K+ and Mn2+; expressed primarily in flowers (Morris et al., 2008).
Eukaryota
Viridiplantae
CAX9 of Arabidopsis thaliana (Q9LJI2)
*2.A.19.4.8









K+ uptake and Na+ transporter, CCX5 (CAX11) (Zhang et al., 2011).

Eukaryota
Viridiplantae
CCX5 of Arabidopsis thaliana (O04034)
*2.A.19.4.9









Na+/K+/Ca2+ exchanger-1 isoform 1, NCKX-1

Eukaryota
Metazoa
SLC24A1 of Homo sapiens
*2.A.19.4.10









Sodium/potassium/calcium exchanger 3 (Na(+)/K(+)/Ca(2+)-exchange protein 3) (Solute carrier family 24 member 3)
Eukaryota
Metazoa
SLC24A3 of Homo sapiens
*2.A.19.4.11









Sodium/potassium/calcium exchanger 2 (Na(+)/K(+)/Ca(2+)-exchange protein 2) (Retinal cone Na-Ca+K exchanger) (Solute carrier family 24 member 2)
Eukaryota
Metazoa
SLC24A2 of Homo sapiens
*2.A.19.4.12









Putative Ca2+:cation exchanger of 1524 aas and an apparent duplication with 27 putative
TMSs and at leaswt 4 repeat units of 4 - 6 TMSs in the arrangement:  1 - 4, 1 - 220 aas; 5 - 9, 240 - 410 aas; 10 - 15, 460 - 650 aas; 16 - 21, 660 - 940 aas; and 22 - 27, 990 - 1200 aas.  It also has a C-terminal PAN-APP domain as in plasminogen.

Eukaryota
Metazoa
Putative Ca2+: cation exchanger of Branchiostoma floridae
*2.A.19.4.13









Uncharacterized protein of 623 aas.

Eukaryota
Pelagophyceae
UP of Aureococcus anophagefferens (Harmful bloom alga)
*2.A.19.4.14









Ca2+:Na+ exchanger, NCX-9 of 651 aas and 14 TMSs.  Plays a role in developmental cell patterning and Ca2+ exchange in mitochondrial (Sharma et al. 2017).

Eukaryota
Metazoa
NCX-9 of Caenorhabditis elegans
*2.A.19.5.1









Putative Ca2+:H+ or Ca2+:Na+ antiporter with two 5 TMS internal repeats (Sääf et al. 2001).

Bacteria
Proteobacteria
ChaB (YrbG) of E. coli
*2.A.19.5.2









Cation (Ca2+/Na+):proton antiporter, ChaA or CaxA (confers both Na+ and Ca2+ resistance) (Wei et al., 2007)
Bacteria
Proteobacteria
ChaA of Alkalimonas amylolytica (Q0ZAI3)
*2.A.19.5.3









Na+:Ca2+ exchanger, NCX_Mj (3-d structure known at 1.9 Å resolution; PDB# 3V5U (Liao et al., 2012). Contains 10 TMSs with two 5 TMS repeats. Four ion binding sites near the center of the protein are present, one specific for Ca2+ and three probably for Na+. Two passageways allow for Na+ and Ca2+ access from the external side.  However see a more recent analysis reported for 2.A.19.8.2 (Nishizawa et al. 2013).  Transport of both Na+ and Ca2+ requires protonation of D240, but this side chain does not coordinate either ion, implying that the ion exchange stoichiometry is 3:1 and that translocation of Na+ across the membrane is electrogenic although transport of Ca2+ is not (Marinelli et al. 2014).

Archaea
Euryarchaeota
NCX_Mj of Methanococcus (Methanocaldococcus) jannaschii (Q57556)
*2.A.19.5.4









Na+/Ca2+ exchanger. Transport is electrogenic with a likely stoichiometry of 3 or more Na+ for each Ca2+ but K+-independent (Besserer et al. 2012).

Archaea
Euryarchaeota
MaX1 of Methanosarcina acetivorans
*2.A.19.6.1









Vacuolar electrogenic Mg2+, Zn2+, Fe2+, and possibly Cd2+:H+ antiporter, MHX (found in the vascular cylinder; may control the partitioning of Mg2+ and Zn2+ between plant organs).  MHX porters are found only in plants and probably have 9 TMSs.  Their properties have been reviewed (Gaash et al. 2013).

Eukaryota
Viridiplantae
MHX of Arabidopsis thaliana
(O22252)
*2.A.19.7.1









Low affinity vacuolar monovalent cation (Na+ (Km=20 mM) or K+(Km=80 mM)):H+ antiporter, Vnx1. (Ca2+ is not transported; plays roles in ion and pH homeostasis) (Cagnac et al., 2007)

Eukaryota
Fungi
Vnx1 of Saccharomyces cerevisiae (P42839)
*2.A.19.7.2









Uncharacterized protein of 739 aas.

Eukaryota
Metazoa
UP of Ornithorhynchus anatinus (Duckbill platypus)
*2.A.19.8.1









Calcium:proton exchanger, CAX(CK31).  The function was demonstrated by purification and reconstitution in liposomes (Ridilla et al. 2012).  The protein forms dimers in the membrane but can be purified as a monomer.  The dimer interface seems to involve TMSs 2 and 6 (Ridilla et al. 2012).

Bacteria
Proteobacteria
CAX(CD31) of Caulobacter sp. strain K31
*2.A.19.8.2









Ca2+:H+ antiporter of 405 aas, CAX_Af.  The inward facing 3-d structure has been solved to 2.3 Å resolution (Nishizawa et al. 2013).  The authors compare this structure to the outward facing 1.9 Å structure of NCX_Mj (TC# 2.A.19.5.3) and suggest that Ca2+ or H+ binds to the cation-binding site mutually exclusively.  The first and sixth TMSs alternately create hydrophilic cavities on the intra- and extracellluar sides of the membrane.  The inward and outward-facing transitions are triggered by ion binding (Nishizawa et al. 2013).

Archaea
Euryarchaeota
Ca2+:H+ antiporter CAX_Af of Archaeoglobus fulgidus
*2.A.19.9.1









Mg2+ transporter (Mg2+-specific channel-like exchanger) of 550 aas (Preston and Kung 1994; Haynes et al. 2002).  Has 10 putative TMSs in a 5 + 5 TMS arrangement and exhibits properties of a channel (Haynes et al. 2002).  The mutant form is called 'eccentric' and exhibits backwards swimming behavior (Preston and Kung 1994). 

Eukaryota
Intramacronucleata
Ca2+-dependent Mg2+ transporter of Paramecium tetraurelia
*2.A.19.9.2









Eukaryota
Intramacronucleata
Tetrahymena thermophila
*2.A.19.10.1









Putative CaCA family member of 368 aas and 10 TMSs

Eukaryota
Dictyosteliida
UP of Dictyostelium discoideum
*2.A.19.10.2









Uncharacterized protein of 518 aas and 10 TMSs

Eukaryota
Metazoa
UP of Trichoplax adhaerens (Trichoplax reptans)