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Gene Review

SLC12A5  -  solute carrier family 12...

Homo sapiens

Synonyms: Electroneutral potassium-chloride cotransporter 2, K-Cl cotransporter 2, KCC2, KIAA1176, Neuronal K-Cl cotransporter, ...
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Disease relevance of SLC12A5


High impact information on SLC12A5

  • NKCC1 expression level versus expression of the Cl(-)-extruding transporter (KCC2) in human and rat cortex showed that Cl(-) transport in perinatal human cortex is as immature as in the rat [6].
  • These neurons are nocispecific, support long-term potentiation and appear to downregulate the K(+)-Cl(-) exporter channel KCC2 following peripheral nerve damage, leading to increased excitability [7].
  • Removal of subplate neurons prevents the developmental upregulation of genes involved in mature, fast GABAergic transmission in cortical layer 4, including GABA receptor subunits and KCC2, and thus prevents the switch to a hyperpolarizing effect of GABA [8].
  • In the spinal cord of wild-type animals, the KCC2 protein was found at inhibitory synapses [9].
  • Several potassium-chloride cotransporters can lower the intracellular chloride concentration [Cl(-)](i), including the neuronal isoform KCC2 [9].

Biological context of SLC12A5

  • The 24-exon SLC12A5 gene is on human chromosome 20q13, and contains a polymorphic dinucleotide repeat within intron 1 near a potential binding site for neuron-restrictive silencing factor [1].
  • Initial and steady state kinetics of hKCC2-injected oocytes were performed in both isotonic and hypotonic conditions, revealing K(m)s for K(+) and Cl(-) of 9.3+/-1.8 mM and 6.8+/-0.9 mM, respectively; both affinities are significantly higher than KCC1 and KCC4 [1].
  • Here we have determined chromosome location of both the human and the mouse genes encoding KCC2, which may assist in future efforts to determine the contribution of KCC2 to inherited human disorders [10].
  • Quantitative RT-PCR analyses of the mRNAs extracted from the human TLE-associated brain regions revealed an up-regulation of NKCC1 mRNA and a down-regulation of KCC2 mRNA in the hippocampal subiculum, compared with the hippocampus proper or the TL neocortex, suggesting an abnormal transcription of Cl(-) transporters in the TLE subiculum [11].
  • Mutagenesis of this region revealed that residues 1021-1035 of KCC2 are sufficient for isotonic transport [12].

Anatomical context of SLC12A5

  • KCC2 (gene symbol SLC12A5) is expressed exclusively in neurons within the central nervous system and abnormalities in its expression have been proposed to play a role in pathological conditions such as epilepsy and neuronal trauma [10].
  • In contrast, oocytes expressing mouse KCC4 do not mediate isotonic K-Cl cotransport but express much higher absolute transport activity than KCC2 oocytes under hypotonic conditions [1].
  • The mRNA levels of NKCC1, an inwardly directed Na(+), K(+)-2Cl(-) cotransporter that facilitates the accumulation of intracellular Cl(-), and of KCC2, an outwardly directed K(+)-Cl(-) cotransporter that extrudes Cl(-), were studied in surgically resected brain specimens from drug-resistant temporal lobe (TL) epilepsy (TLE) patients [11].
  • The KCC3 mRNA was highly expressed in brain, heart, skeletal muscle, and kidney, showing a distinct pattern and size from KCC1 and KCC2 [13].
  • Finally, measurements of the GABA reversal potential in different starburst dendritic compartments indicate that the GABA reversal potential at the distal dendrite is more hyperpolarized than at the proximal dendrite due to KCC2 activity [14].

Associations of SLC12A5 with chemical compounds

  • The relative expression level of the neuron-specific SLC12A5 and the Na(+)-K(+)-2Cl(-) cotransporter SLC12A2 appears to determine whether neurons respond to GABA with a depolarizing, excitatory response or with a hyperpolarizing, inhibitory response [15].
  • The neuron-specific K(+)-Cl(-) cotransporter KCC2 plays a crucial role in determining intracellular chloride activity and thus the neuronal response to gamma-aminobutyric acid and glycine [12].
  • Swelling-activated K(+)-Cl(-) cotransport is abrogated by calyculin A, whereas isotonic transport mediated by KCC chimeras and KCC2 is completely resistant to this serine-threonine phosphatase inhibitor [12].
  • This conversion results from a gradual decrease in the chloride electrochemical equilibrium potential (ECl) of developing neurons, which correlates to an increase in the expression or activity of the potassium chloride cotransporter, KCC2 [16].
  • Here we determined if the GABA switch correlates with the developmental expression patterns of KCC2, the chloride extruder K(+)-Cl(-) cotransporter, and NKCC, the chloride accumulator Na(+)-K(+)-Cl(-) cotransporter [3].

Regulatory relationships of SLC12A5

  • Immunoblots of ferret retina showed that KCC2 upregulated in an exponential manner similar to synaptophysin (a synaptic marker) [3].

Other interactions of SLC12A5

  • In addition, factors influencing the trafficking and kinetic modulation of KCC2 as well as activation/deactivation of CAVII are obvious candidates in the ionic modulation of GABAergic responses [17].
  • Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII [17].
  • KCC3 shares 75-76% identity at the amino acid level with human, pig, rat, and rabbit KCC1 and 67% identity with rat KCC2 [18].
  • The down-regulation of KCC2 under pathophysiological conditions (epilepsy, damage) in mature neurones seems to reflect a 'recapitulation' of early developmental mechanisms, which may be a prerequisite for the re-establishment of connectivity in damaged brain tissue [17].
  • We show here that selective blockade of the NKCC2 and KCC2 cotransporters located on starburst dendrites consistently hyperpolarized and depolarized the starburst cells, respectively, and greatly reduced or eliminated their directionally selective light responses [14].

Analytical, diagnostic and therapeutic context of SLC12A5

  • Of the four KCC genes known to encode the respective proteins and their spliced variants, RT-PCR with both rat and human primers revealed the predicted cDNA fragments of KCC1, KCC3a, KCC3b, and KCC4 but not KCC2 in both HLE-B3 cells and in human lens tissue extracts from cataractous patients [19].
  • Northern blot analysis using a KCC2-specific cDNA probe revealed a very highly expressed approximately5.6-kilobase transcript only in brain [5].
  • In situ hybridization studies demonstrated that the KCC2 transcript was expressed at high levels in neurons throughout the central nervous system, including CA1-CA4 pyramidal neurons of the hippocampus, granular cells and Purkinje neurons of the cerebellum, and many groups of neurons throughout the brainstem [5].
  • K-Cl cotransporter KCC2 immunohistochemistry revealed a developmental increase of staining in the area of lumbar motoneurons between P0 and P7 in cord-intact animals; this increase was not observed after spinal cord transection [20].
  • To explore a possible role of KCC2-dependent inhibition in anesthetic-induced impairment of LTP, we used field excitatory postsynaptic potentials (fEPSP) recording and immunoblotting to study the effect of propofol on LTP maintenance and KCC2 expression in CA1 region of rat hippocampal slices [21].


  1. Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter. Song, L., Mercado, A., Vázquez, N., Xie, Q., Desai, R., George, A.L., Gamba, G., Mount, D.B. Brain Res. Mol. Brain Res. (2002) [Pubmed]
  2. Human and murine phenotypes associated with defects in cation-chloride cotransport. Delpire, E., Mount, D.B. Annu. Rev. Physiol. (2002) [Pubmed]
  3. Regulation of KCC2 and NKCC during development: Membrane insertion and differences between cell types. Zhang, L.L., Fina, M.E., Vardi, N. J. Comp. Neurol. (2006) [Pubmed]
  4. Expression changes of cation chloride cotransporters in the rat spinal cord following intraplantar formalin. Nomura, H., Sakai, A., Nagano, M., Umino, M., Suzuki, H. Neurosci. Res. (2006) [Pubmed]
  5. Molecular characterization of a putative K-Cl cotransporter in rat brain. A neuronal-specific isoform. Payne, J.A., Stevenson, T.J., Donaldson, L.F. J. Biol. Chem. (1996) [Pubmed]
  6. NKCC1 transporter facilitates seizures in the developing brain. Dzhala, V.I., Talos, D.M., Sdrulla, D.A., Brumback, A.C., Mathews, G.C., Benke, T.A., Delpire, E., Jensen, F.E., Staley, K.J. Nat. Med. (2005) [Pubmed]
  7. Setting the tone: superficial dorsal horn projection neurons regulate pain sensitivity. Mantyh, P.W., Hunt, S.P. Trends Neurosci. (2004) [Pubmed]
  8. Subplate neurons regulate maturation of cortical inhibition and outcome of ocular dominance plasticity. Kanold, P.O., Shatz, C.J. Neuron (2006) [Pubmed]
  9. Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. Hübner, C.A., Stein, V., Hermans-Borgmeyer, I., Meyer, T., Ballanyi, K., Jentsch, T.J. Neuron (2001) [Pubmed]
  10. Chromosomal localization of SLC12A5/Slc12a5, the human and mouse genes for the neuron-specific K(+)-Cl(-) cotransporter (KCC2) defines a new region of conserved homology. Sallinen, R., Tornberg, J., Putkiranta, M., Horelli-Kuitunen, N., Airaksinen, M.S., Wessman, M. Cytogenet. Cell Genet. (2001) [Pubmed]
  11. Anomalous levels of Cl- transporters in the hippocampal subiculum from temporal lobe epilepsy patients make GABA excitatory. Palma, E., Amici, M., Sobrero, F., Spinelli, G., Di Angelantonio, S., Ragozzino, D., Mascia, A., Scoppetta, C., Esposito, V., Miledi, R., Eusebi, F. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  12. A C-terminal domain in KCC2 confers constitutive K+-Cl- cotransport. Mercado, A., Broumand, V., Zandi-Nejad, K., Enck, A.H., Mount, D.B. J. Biol. Chem. (2006) [Pubmed]
  13. Cloning, characterization, and chromosomal location of a novel human K+-Cl- cotransporter. Hiki, K., D'Andrea, R.J., Furze, J., Crawford, J., Woollatt, E., Sutherland, G.R., Vadas, M.A., Gamble, J.R. J. Biol. Chem. (1999) [Pubmed]
  14. From the Cover: Dendritic compartmentalization of chloride cotransporters underlies directional responses of starburst amacrine cells in retina. Gavrikov, K.E., Nilson, J.E., Dmitriev, A.V., Zucker, C.L., Mangel, S.C. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  15. Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. Hebert, S.C., Mount, D.B., Gamba, G. Pflugers Arch. (2004) [Pubmed]
  16. KCC2 expression in immature rat cortical neurons is sufficient to switch the polarity of GABA responses. Lee, H., Chen, C.X., Liu, Y.J., Aizenman, E., Kandler, K. Eur. J. Neurosci. (2005) [Pubmed]
  17. Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII. Rivera, C., Voipio, J., Kaila, K. J. Physiol. (Lond.) (2005) [Pubmed]
  18. Molecular cloning and functional characterization of KCC3, a new K-Cl cotransporter. Race, J.E., Makhlouf, F.N., Logue, P.J., Wilson, F.H., Dunham, P.B., Holtzman, E.J. Am. J. Physiol. (1999) [Pubmed]
  19. KCC isoforms in a human lens epithelial cell line (B3) and lens tissue extracts. Misri, S., Chimote, A.A., Adragna, N.C., Warwar, R., Brown, T.L., Lauf, P.K. Exp. Eye Res. (2006) [Pubmed]
  20. Inhibitory postsynaptic potentials in lumbar motoneurons remain depolarizing after neonatal spinal cord transection in the rat. Jean-Xavier, C., Pflieger, J.F., Liabeuf, S., Vinay, L. J. Neurophysiol. (2006) [Pubmed]
  21. Changes of K(+)-Cl(-) cotransporter 2 (KCC2) and circuit activity in propofol-induced impairment of long-term potentiation in rat hippocampal slices. Wang, W., Wang, H., Gong, N., Xu, T.L. Brain Res. Bull. (2006) [Pubmed]
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