TCDB is operated by the Saier Lab Bioinformatics Group
TCIDNameDomainKingdom/PhylumProtein(s)
*2.A.30.1.1









NaCl/KCl symporter; the orthologue in humans when mutated can be responsible for Bartter syndrome, an autosomal recessive disease (Stechman et al., 2007).

Eukaryota
Metazoa
NaCl/KCl cotransporter of Rattus norvegicus
*2.A.30.1.2









Solute carrier family 12 member 1 (Bumetanide-sensitive sodium-(potassium)-chloride cotransporter 2) (Kidney-specific Na-K-Cl symporter, NKCC2) Mutations cause type I Bartter syndrome (BS), a life threatening kidney disease featuring arterial hypotension along with electrolyte abnormalities (Adachi et al. 2007).  An OS9-mediated ERAD pathway in renal cells degrades immature NKCC2 proteins (Seaayfan et al. 2015). Regulated by AMPK (see 8.A.104.1.1).

Eukaryota
Metazoa
SLC12A1 of Homo sapiens
*2.A.30.1.3









Sodium-coupled cation-chloride cotransporter of 859 aas and 11 TMSs.  There are three paralogues (Piermarini et al. 2017).

CCC of Aedes aegypti (Yellowfever mosquito) (Culex aegypti)
*2.A.30.1.4









NaCl/KCl symporter (basolateral), NKCC1 (may also transport NH4+ and water); (Worrell et al., 2008; Hamann et al., 2010). Loop diuretic and ion binding residues have been identified (Somasekharan et al., 2012).  NKCC1 is the major Cl--loader responsible for the depolarizing action of GABA/glycine receptors at postnatal days 3-5 in cochlear nucleus neurons (Witte et al. 2014). Stimulated by ammonia (Hertz et al. 2015).  NKCC maintains Cl- gradients to sustain pacemaker activity (TC# 1.A.1.5.10) in interstitial cells of Cajal (Zhu et al. 2016).

Eukaryota
Metazoa
SLC12A2 of Homo sapiens
*2.A.30.1.5









NaCl/KCl symporter
Eukaryota
Metazoa
NaCl/KCl symporter of Squalus acanthias (Shark)
*2.A.30.1.6









solute carrier family 12 (potassium/chloride transporters), member 9
Eukaryota
Metazoa
SLC12A9 of Homo sapiens
*2.A.30.1.7









solute carrier family 12 (potassium/chloride transporters), member 8
Eukaryota
Metazoa
SLC12A8 of Homo sapiens
*2.A.30.1.8









Na+,K+,Cl--cotransporter, NKCC or Slc12a2, of 1120 aas and 12 TMSs.  Ion transport via an ortholog is oxygen-sensitive and is regulated by two different oxygen sensors in crucian carp (Carassius carassius) (Berenbrink et al. 2006).

Eukaryota
Metazoa
NKCC of Danio rerio (Zebrafish) (Brachydanio rerio)
*2.A.30.1.9









Possible NaCl/KCl symporter
Eukaryota
Metazoa
NaCl/KCl cotransporter of Manduca sexta
*2.A.30.1.10









The Na+/K+Cl- cotransporter, NKCC1 of 1036 aas and 11 or 12 TMSs. In several insects, it is involved in prostaglandin E2-promoted immune responses. PGE2 mediates oenocytoid cell lysis (a class of lepidopteran hemocytes: OCL) via a specific membrane receptor to release inactive prophenoloxidase (PPO) into the hemolymph (Shrestha et al. 2015).

 

Eukaryota
Metazoa
NKCC1 of Bombyx mori (Silk moth)
*2.A.30.1.11









NaCl symporter (activated by phosphorylation of the N-terminal domain upon Cl- depletion (Pacheco-Alvarez et al., 2006))
Eukaryota
Metazoa
NaCl cotransporter of Rattus norvegicus
*2.A.30.1.12









Electroneutral NaCl symporter, NCC (Gitelman syndrome transporter). NCC is also an Interleukin-18 (IL18)-binding protein that collaborates with the IL18 receptor in cell signaling, inflammatory molecule expression, and experimental atherogenesis (Wang et al. 2015). NCC and the α- and γ-subunits of the epithelial Na+ channel, which together determine salt balance and blood pressure, directly interact with each other with functional consequences (Mistry et al. 2016).

Eukaryota
Metazoa
SLC12A3 (NCC) of Homo sapiens
*2.A.30.1.13









KCl symporter, KCC1. Water can be cotransported with KCl (Mollajew et al., 2010).

Eukaryota
Metazoa
KCl cotransporter KCC1 of Rattus norvegicus (Q63632)
*2.A.30.1.14









KCl symporter KCC2. It influences postsynaptic AMPA receptor content and lateral diffusion in dendritic spines (Gauvain et al., 2011). It plays a role in inhibitory and excitatory neurotransmission in neurons (Chamma et al., 2012). KCC2 transport activity requires the highly conserved L(675) in the C-terminal β1 strand (Döding et al., 2012). Direct physical coupling between the GABA-A receptor and the KCC2 chloride transporter underlies ionic plasticity in cerebellar purkinje neurons in response to brain-derived neurotrophic factor (BDNF) (Huang et al., 2013).  KCC2 is neuron-specific and is essential for Cl(-) homeostasis and fast inhibitory synaptic transmission in the mature CNS. KCC2 is regulated by the single-pass transmembrane protein neuropilin and tolloid like-2 (Neto2). Neto2 is required to maintain the normal abundance of KCC2 and specifically associates with the active oligomeric form of the transporter (Ivakine et al. 2013). Loss of the Neto2:KCC2 interaction reduced KCC2-mediated Cl- extrusion, resulting in decreased synaptic inhibition in hippocampal neurons.  KCC2 mediates the efflux of Cl-out of neurons and plays a role in inhibitory GABAergic and glycinergic neurotransmission. It also participates in the regulation of various physiological processes of neurons, including cell migration, dendritic outgrowth, spine morphology, and dendritic synaptogenesis (Wu et al. 2016). Down-regulation of KCC2 is associated with multiple neurological diseases and is particularly relevant to acute central nervous system (CNS) injury.

Eukaryota
Metazoa
KCl cotransporter KCC2 of Rattus norvegicus
*2.A.30.1.15









KCl symporter, KCC3 (Andermann Syndrome protein)
Eukaryota
Metazoa
SLC12A6 of Homo sapiens
*2.A.30.1.16









Solute carrier family 12 member 7 (Electroneutral potassium-chloride cotransporter 4) (K-Cl cotransporter 4)
Eukaryota
Metazoa
SLC12A7 of Homo sapiens
*2.A.30.1.17









Solute carrier family 12 member 4 (Electroneutral potassium-chloride cotransporter 1, KCC1) (Erythroid K-Cl cotransporter 1) (hKCC1).  It is activated by cell swelling and may contribute to cell volume homeostasis as well as being involved in the regulation of basolateral Cl- exit in NaCl absorbing epithelia. Isoform 4 has no transport activity. The kinase, WNK3, activates NKCC1/2 and NCC but inhibits the KCCs (Cruz-Rangel et al. 2011).  Liu et al. 2019 presented cryo-EM structures of human KCC1 in potassium chloride or sodium chloride at 2.9- to 3.5-Å resolution. KCC1 exists as a dimer, with both extracellular and transmembrane domains involved in dimerization. The structural and functional analyses, along with computational studies, reveal one potassium site and two chloride sites in KCC1, which are all required for the ion transport activity. The structure reveals an inward-facing conformation, with the extracellular gate occluded. The KCC1 structures allowed the authors to model a potential ion transport mechanism in KCCs and provide a blueprint for drug design (Liu et al. 2019).

Eukaryota
Metazoa
SLC12A4 of Homo sapiens
*2.A.30.1.18









Solute carrier family 12 member 5 (Electroneutral potassium-chloride cotransporter 2) (K-Cl cotransporter 2) (hKCC2) (Neuronal K-Cl cotransporter). Direct physical coupling between the GABA-A receptor and the KCC2 chloride transporter underlies ionic plasticity in cerebellar purkinje neurons in response to brain-derived neurotrophic factor (BDNF) (Huang et al., 2013).  KCC2 is responsible for maintaining low Cl- concentrations in neurons of the CNS.  Loss of activity of this transporter provides a mechanism underlying several neurological and psychiatric disorders, including epilepsy, motor spasticity, stress, anxiety, schizophrenia, morphine-induced hyperalgesia and chronic pain (Gagnon et al. 2013).  Mediates chloride extrusion in mature neurons, and it regulates the development and morphology of dendritic spines through structural interactions with the actin cytoskeleton  through interaction with the b isoform of Rac/Cdc42 guanine nucleotide exchange factor, β-PIX (Llano et al. 2015). KCC2 affects the maturation of glycinergic synapses in cultured spinal cord neurons (Schwale et al. 2016). Kainate receptors regulate KCC2 expression in the hippocampus (Pressey et al. 2017).

Eukaryota
Metazoa
SLC12A5 of Homo sapiens
*2.A.30.1.19









K+,Cl--cotransporter, KCC or Slc12a5b of 1117 aas and 12 TMSs. Ion transport via an ortholog is oxygen-sensitive and is regulated by two different oxygen sensors in crucian carp (Carassius carassius) (Berenbrink et al. 2006).

Eukaryota
Metazoa
KCC of Danio rerio (Zebrafish) (Brachydanio rerio)
*2.A.30.1.20









Possible NaCl/KCl or KCl symporter, Axi4
Eukaryota
Viridiplantae
Axi4 of Nicotiana tabacum
*2.A.30.1.21









Potassium/chloride cotransporter, KCC2 of 1139 aas and 12 TMSs. It mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl- homeostasis. As a 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 (Puskarjov et al. 2014). Postnatal changes in expression in the forebrain of mice bearing a mutant nicotinic subunit has been linked to Sleep-Related Epilepsy (Amadeo et al. 2018). KCC2 regulates neuronal excitability and hippocampal activity via interaction with Task-3 channels (Goutierre et al. 2019).

 

Eukaryota
Metazoa
KCC2 of Homo sapiens