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Gene Review

Slc12a5  -  solute carrier family 12, member 5

Mus musculus

Synonyms: Electroneutral potassium-chloride cotransporter 2, K-Cl cotransporter 2, KCC2, Kcc2, Kiaa1176, ...
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Disease relevance of Slc12a5

  • We demonstrate that animals deficient in KCC2 exhibit frequent generalized seizures and die shortly after birth [1].
  • To produce various types of gene-targeting constructions rapidly and with minimum effort, we developed a strategy, that utilizes a highly efficient in vitro transposition reaction of phage Mu, and tested it in a targeting of the mouse Kcc2 gene locus [2].
  • KCC2 was expressed wherever E(Cl) is either known or predicted to be negative to E(rest) (ganglion cells, bipolar axons, and OFF bipolar dendrites), whereas NKCC was expressed wherever E(Cl) is either known or predicted to be positive to E(rest) (horizontal cells and ON bipolar dendrites) [3].

High impact information on Slc12a5

  • This loss of GABAergic and glycinergic synaptic transmission does not impair the development of inhibitory synapses or the expression of KCC2, the K+ -Cl- cotransporter known to be essential for the establishment of inhibitory neurotransmission [4].
  • By expression studies in Xenopus oocytes, we show that kinase-active WNK3 increases Cl(-) influx via NKCC1, and that it inhibits Cl(-) exit through KCC1 and KCC2; kinase-inactive WNK3 has the opposite effects [5].
  • BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2 [6].
  • By combining the information from overlapping minicontigs, the sequence of the entire 10,288-bp region of mouse genome including six exons of mouse Kcc2 gene was obtained [7].
  • Membrane proteins that typically extrude chloride (KCC-2 cotransporter, CLC-2 channel) were absent from the GT1-7 immortalized GnRH cell line and GnRH neurons in situ or were not localized to the proper cell compartment for function [8].

Biological context of Slc12a5

  • In transgenic mice, however, KCC2 reporters with or without deletion of the NRSE(KCC2) were expressed exclusively in neurones and predominantly in the CNS with a similar pattern and developmental up-regulation as endogenous KCC2 [9].
  • Overexpression of neurone-restrictive silencer factor repressed the reporter activity in vitro, apparently via a neurone restrictive silencer element (NRSE(KCC2)) within intron 1 of the mouse KCC2 gene [9].
  • Moreover, a third transgene with just a 1.4-kb KCC2 promoter region lacking the NRSE(KCC2)-bearing intron 1 was still expressed predominantly in neural tissues [9].
  • Here, we show that the KCC2 gene (alias SLC12a5) has multiple transcription start sites and characterize the activity of 6.8 kb of mouse KCC2 gene regulatory sequence (spanning 1.4 kb upstream from exon 1 to exon 2) using luciferase reporters [9].
  • Behavioural phenotypes of hypomorphic KCC2-deficient mice [10].

Anatomical context of Slc12a5


Associations of Slc12a5 with chemical compounds

  • Interestingly, whereas BDNF does not alter the expression of GABA and glutamate ionotropic receptors, it does raise the expression of the recently cloned K(+)/Cl(-) KCC2 co-transporter, which is responsible for the conversion of GABA responses from depolarizing to inhibitory, through the control of the Cl(-) potential [6].
  • The K+/Cl- co-transporter KCC2 maintains the low intracellular chloride concentration required for fast synaptic inhibition and is exclusively expressed in neurones of the CNS [9].
  • Heterogeneous expression of the potassium-chloride cotransporter KCC2 in gonadotropin-releasing hormone neurons of the adult mouse [11].
  • KCC2, is exclusively expressed in neurons where it is thought to drive intracellular Cl- to low concentrations and shift the reversal potential for Cl- conductances such as GABA(A) or glycine receptor channels, thus participating in the postnatal development of inhibitory mechanisms in the brain [1].
  • KCC2 activity is thought to depend on phosphorylation by endogenous tyrosine kinases [12].

Regulatory relationships of Slc12a5

  • Indeed, NCBE is expressed very early in CNS neurons and precedes the expression of KCC2 [14].
  • A recent in vitro study [Ganguly et al. (2001) Cell, 105, 521-532] showed that KCC2 expression may be under the trophic control of GABAA receptor-mediated transmission [15].

Other interactions of Slc12a5

  • As NCBE, a sodium-dependent chloride-bicarbonate exchanger, also lowers [Cl(-)](i) and may thus modulate the GABA-response, we analyzed its expression during prenatal mouse development before establishment of the mature KCC2 expression [14].
  • Blockade of GABAA-mediated transmission with picrotoxin did not affect the expression levels of KCC2 protein either [15].

Analytical, diagnostic and therapeutic context of Slc12a5


  1. Hyperexcitability and epilepsy associated with disruption of the mouse neuronal-specific K-Cl cotransporter gene. Woo, N.S., Lu, J., England, R., McClellan, R., Dufour, S., Mount, D.B., Deutch, A.Y., Lovinger, D.M., Delpire, E. Hippocampus. (2002) [Pubmed]
  2. Construction of gene-targeting vectors: a rapid Mu in vitro DNA transposition-based strategy generating null, potentially hypomorphic, and conditional alleles. Vilen, H., Eerikäinen, S., Tornberg, J., Airaksinen, M.S., Savilahti, H. Transgenic Res. (2001) [Pubmed]
  3. Evidence that different cation chloride cotransporters in retinal neurons allow opposite responses to GABA. Vardi, N., Zhang, L.L., Payne, J.A., Sterling, P. J. Neurosci. (2000) [Pubmed]
  4. A shared vesicular carrier allows synaptic corelease of GABA and glycine. Wojcik, S.M., Katsurabayashi, S., Guillemin, I., Friauf, E., Rosenmund, C., Brose, N., Rhee, J.S. Neuron (2006) [Pubmed]
  5. WNK3 modulates transport of Cl- in and out of cells: implications for control of cell volume and neuronal excitability. Kahle, K.T., Rinehart, J., de Los Heros, P., Louvi, A., Meade, P., Vazquez, N., Hebert, S.C., Gamba, G., Gimenez, I., Lifton, R.P. Proc. Natl. Acad. Sci. U.S.A. (2005) [Pubmed]
  6. BDNF regulates spontaneous correlated activity at early developmental stages by increasing synaptogenesis and expression of the K+/Cl- co-transporter KCC2. Aguado, F., Carmona, M.A., Pozas, E., Aguiló, A., Martínez-Guijarro, F.J., Alcantara, S., Borrell, V., Yuste, R., Ibañez, C.F., Soriano, E. Development (2003) [Pubmed]
  7. An efficient DNA sequencing strategy based on the bacteriophage mu in vitro DNA transposition reaction. Haapa, S., Suomalainen, S., Eerikäinen, S., Airaksinen, M., Paulin, L., Savilahti, H. Genome Res. (1999) [Pubmed]
  8. Activation of A-type gamma-aminobutyric acid receptors excites gonadotropin-releasing hormone neurons. DeFazio, R.A., Heger, S., Ojeda, S.R., Moenter, S.M. Mol. Endocrinol. (2002) [Pubmed]
  9. Neuronal K+/Cl- co-transporter (KCC2) transgenes lacking neurone restrictive silencer element recapitulate CNS neurone-specific expression and developmental up-regulation of endogenous KCC2 gene. Uvarov, P., Pruunsild, P., Timmusk, T., Airaksinen, M.S. J. Neurochem. (2005) [Pubmed]
  10. Behavioural phenotypes of hypomorphic KCC2-deficient mice. Tornberg, J., Voikar, V., Savilahti, H., Rauvala, H., Airaksinen, M.S. Eur. J. Neurosci. (2005) [Pubmed]
  11. Heterogeneous expression of the potassium-chloride cotransporter KCC2 in gonadotropin-releasing hormone neurons of the adult mouse. Leupen, S.M., Tobet, S.A., Crowley, W.F., Kaila, K. Endocrinology (2003) [Pubmed]
  12. Expression of the KCl cotransporter KCC2 parallels neuronal maturation and the emergence of low intracellular chloride. Stein, V., Hermans-Borgmeyer, I., Jentsch, T.J., Hübner, C.A. J. Comp. Neurol. (2004) [Pubmed]
  13. Malfunction of respiratory-related neuronal activity in Na+, K+-ATPase alpha2 subunit-deficient mice is attributable to abnormal Cl- homeostasis in brainstem neurons. Ikeda, K., Onimaru, H., Yamada, J., Inoue, K., Ueno, S., Onaka, T., Toyoda, H., Arata, A., Ishikawa, T.O., Taketo, M.M., Fukuda, A., Kawakami, K. J. Neurosci. (2004) [Pubmed]
  14. Expression of the sodium-driven chloride bicarbonate exchanger NCBE during prenatal mouse development. Hübner, C.A., Hentschke, M., Jacobs, S., Hermans-Borgmeyer, I. Gene Expr. Patterns (2004) [Pubmed]
  15. Developmental up-regulation of KCC2 in the absence of GABAergic and glutamatergic transmission. Ludwig, A., Li, H., Saarma, M., Kaila, K., Rivera, C. Eur. J. Neurosci. (2003) [Pubmed]
  16. 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]
  17. Expression and function of chloride transporters during development of inhibitory neurotransmission in the auditory brainstem. Balakrishnan, V., Becker, M., Löhrke, S., Nothwang, H.G., Güresir, E., Friauf, E. J. Neurosci. (2003) [Pubmed]
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