Chloride potassium symporter 5

Chloride potassium symporter 5
Solute carrier family 12 (potassium/chloride transporter), member 5
Symbols SLC12A5; KCC2; KIAA1176
External IDs OMIM606726 MGI1862037 HomoloGene10665 GeneCards: SLC12A5 Gene
RNA expression pattern
PBB GE SLC12A5 210040 at tn.png
More reference expression data
Species Human Mouse
Entrez 57468 57138
Ensembl ENSG00000124140 ENSMUSG00000017740
UniProt Q9H2X9 Q3UHQ2
RefSeq (mRNA) NM_001134771.1 NM_020333.2
RefSeq (protein) NP_001128243.1 NP_065066.2
Location (UCSC) Chr 20:
44.65 – 44.69 Mb
Chr 2:
164.79 – 164.83 Mb
PubMed search [1] [2]

Potassium-chloride transporter member 5 (aka: KCC2 and SLC12A5) is a neuron-specific chloride potassium symporter responsible for establishing the chloride ion gradient in neurons through the maintenance of low intracellular chloride concentrations[1]. It is a critical mediator of synaptic inhibition, cellular protection against excitotoxicity[2][3] and may also act as a modulator of neuroplasticity.[4][5][6] Potassium-chloride transporter member 5 is also known by the names: KCC2 (potassium chloride cotransporter 2) for its ionic substrates, and SLC12A5 for its genetic origin from the SLC12A5 gene in humans.[1]

Animals with reduced expression of this transporter exhibit severe motor deficits, epileptiform activity, and spasticity.[4] KCC2 knockout animals, in which KCC2 is completely absent, die postnatally due to respiratory failure.[4]



KCC2 is a neuron-specific membrane protein expressed throughout the central nervous system, including the hippocampus, hypothalamus, brainstem, and motoneurons of the ventral spinal cord.[5]

At the subcellular level, KCC2 has been found in membranes of the somata and dendrites of neurons,[7][4] with no evidence of expression on axons.[4] KCC2 has also been shown to colocalize with GABAA receptors, which serve as ligand-gated ion channels to allow chloride ion movement across the cell membrane. Under normal conditions, the opening of GABAA receptors permits the hyperpolarizing influx of chloride ions to inhibit postsynaptic neurons from firing.[3]

Counterintuitively, KCC2 has also been shown to colocalize at excitatory synapses.[2] One suggested explanation for such colocalization is a potential protective role of KCC2 against excitotoxicity.[2][3] Ion influx due to the excitatory synaptic stimulation of ion channels in the neuronal membrane causes osmotic swelling of cells as water is drawn in alongside the ions. KCC2 may help to eliminate excess ions from the cell in order to re-establish osmotic homeostasis.


KCC2 is a member of the cation-chloride cotransporter (CCC) superfamily of proteins.[8]

As with all CCC proteins, KCC2 is an integral membrane protein with 12 transmembrane domains and both N- and C-terminal cytoplasmic domains. The terminal cytoplasmic domains can be phosphorylated by kinases within the neuron for rapid regulation.

Two Isoforms: KCC2a, KCC2b

There are two isoforms of KCC2: KCC2a and KCC2b.[4][9] The two isoforms arise from alternative promoters on the SLC12A5 gene and differential splicing of the first mRNA exon.[4][9] The isoforms differ in their N-termini, with the KCC2a form constituting the larger of the two splice variants.[10]

KCC2a levels remain relatively constant during pre- and postnatal development.[10]

KCC2b, on the other hand, is scarcely present during prenatal development and is strongly upregulated during postnatal development. The upregulation of KCC2b expression is thought to be responsible for the “developmental shift” observed in mammals from depolarizing postsynaptic effects of inhibitory synapses in early neural networks to hyperpolarizing effects in mature neural networks.[4]

KCC2b knockout mice can survive up to postnatal day 17 (P17) due to the presence of functional KCC2a alone, but they exhibit low body weight, motor deficits and generalized seizures.[4] Complete KCC2 knockouts (both KCC2a and KCC2b absent) die after birth due to respiratory failure.[4]


Both KCC2 isoforms can form homomultimers, or heteromultimers with other K-Cl symporters on the cell membrane to maintain chloride homeostasis in neurons.[1] Dimers, trimers, and tetramers involving KCC2 have been identified in brainstem neurons.[11] Oligomerization may play an important role in transporter function and activation, as it has been observed that the oligomer to monomer ratio increases in correlation to the development of the chloride ion gradient in neurons.[11]

Developmental changes in expression

KCC2 levels are low during mammalian embryonic development, when neural networks are still being established and neurons are highly plastic (changeable). During this stage, intracellular chloride ion concentrations are high due to low KCC2 expression and high levels of a transporter known as NKCC1 (Na+/K+ chloride cotransporter 1), which moves chloride ions into cells.[12] Thus, during embryonic development, the chloride gradient is such that stimulation of GABAA receptors and glycine receptors at inhibitory synapses causes chloride ions to flow out of cells, making the internal neuronal environment less negative (ie. more depolarized) than it would be at rest. At this stage, GABAA receptors and glycine receptors act as excitatory rather than inhibitory effectors on postsynaptic neurons, resulting in depolarization and hyperexcitability of neural networks.[4][5][6]

During postnatal development, KCC2 levels are strongly upregulated while NKCC1 levels are down regulated.[12] This change in expression correlates to a developmental shift of the chloride ion concentration within neurons from high to low intracellular concentration. Effectively, as the chloride ion concentration is reduced, the chloride gradient across the cellular membrane is reversed such that GABAA receptor and glycine receptor stimulation causes chloride ion influx, making the internal neuronal environment more negative (ie. more hyperpolarized) than it would be at rest. This is the developmental shift of inhibitory synapses from the excitatory postsynaptic responses of the early neural development phase to the inhibitory postsynaptic responses observed throughout maturity.


Current literature suggests that KCC2 serves three primary roles within neurons:

  1. Establishing the chloride ion gradient necessary for postsynaptic inhibition
  2. As a protective mechanism against stimulation-induced excitotoxicity
  3. As a regulator of neuroplasticity and morphogenicity

Postsynaptic inhibition

KCC2 is a potassium (K+)/chloride (Cl-) symporter that maintains chloride homeostasis in neurons. The electrochemical chloride gradient established by KCC2 activity is crucial for classical postsynaptic inhibition through GABAA receptors and glycine receptors in the central nervous system. KCC2 utilizes the potassium gradient generated by the Na+/K+ pump to drive chloride extrusion from neurons.[4] In fact, any disruption of the neuronal K+ gradient would indirectly affect KCC2 activity.

Loss of KCC2 following neuronal damage (ie. ischemia, spinal cord damage, physical trauma to the central nervous system) results in the loss of inhibitory regulation and the subsequent development of neuronal hyperexcitability, motor spasticity, and seizure-like activity[5] as GABAA receptors and glycine receptors revert from hyperpolarizing to depolarizing postsynaptic effects.

Cellular protection

High levels of stimulation and subsequent ionic influx through activated ion channels can result in cellular swelling as osmotically-obliged water is drawn into neurons along with ionic solutes. This phenomenon is known as excitotoxicity.[2] KCC2 has been shown to be activated by cell-swelling, and may therefore play a role in eliminating excess ions following periods of high stimulation in order to maintain steady-state neuronal volume and prevent cells from bursting.[2]

This role may also account for the fact that KCC2 has been known to colocalize near excitatory synapses, even though its primary role is to establish the chloride gradient for postsynaptic inhibition.[2][3]


KCC2 may play a role in dendritic development within the central nervous system. Studies on hippocampal tissue in KCC2 knockout animals demonstrate that neurons lacking KCC2 have stunted dendritic growth and malformed dendritic spines.[4] Excitatory synapses characteristically occur on dendritic spines, and therefore KCC2 may have an effect on the formation of excitatory synapses during development due to its influence on the morphology of developing neurons.

It has been proposed that the downregulation of KCC2 observed following neuronal trauma, and the consequent depolarizing shift of GABAA-mediated synapses, may be an aspect of neuronal de-differentiation. De-differentiation of damaged portions of the nervous system would allow for neuronal networks to return to higher levels of plasticity in order to rewire of surviving neurons to compensate for damage in the network.[4][5][6]


Transcriptional regulation: TrkB receptor signalling

KCC2 is transcriptionally downregulated following central nervous system injury by the TrkB receptor signalling transduction cascade (activated by BDNF and NT-4/5).[13][14][15]

Post-translational regulation: phosphorylation

It is conventionally thought that phosphorylation inactivates or downregulates KCC2, however there is recent evidence to suggest that phosphorylation at different sites on the KCC2 protein determines different regulational outcomes:

  • Wnk1/ Wnk3 and tyrosine kinase (ie. TrkB) phosphorylation downregulates KCC2 activity.[13][14][15][16]
  • PKC phosphorylation of the C-terminus Ser940 residue of the KCC2 protein upregulates KCC2 activity by increasing surface stability.[4]

KCC2 has an extremely high rate of turnover at the plasmalemma (minutes),[4] suggesting that phosphorylation serves as the primary mechanism for rapid regulation.

Activity-dependent downregulation

KCC2 is downregulated by excitatory glutamate activity on NMDA receptor activity and Ca2+ influx.[16][6]

Glutamate release occurs not only at excitatory synapses, but is also known to occur after neuronal damage or ischemic insult.[6] Thus, activity-dependent downregulation may be the underlying mechanism by which KCC2 downregulation occurs following central nervous system injury.

See also


  1. ^ a b c "Entrez Gene: SLC12A5 solute carrier family 12, (potassium-chloride transporter) member 5". 
  2. ^ a b c d e f Watanabe M, Wake H, Moorhouse AJ, Nabekura J (October 2009). "Clustering of neuronal K+-Cl- cotransporters in lipid rafts by tyrosine phosphorylation". J. Biol. Chem. 284 (41): 27980–8. doi:10.1074/jbc.M109.043620. PMC 2788850. PMID 19679663. 
  3. ^ a b c d Gulyás AI, Sík A, Payne JA, Kaila K, Freund TF (June 2001). "The KCl cotransporter, KCC2, is highly expressed in the vicinity of excitatory synapses in the rat hippocampus". Eur. J. Neurosci. 13 (12): 2205–17. doi:10.1046/j.0953-816x.2001.01600.x. PMID 11454023. 
  4. ^ a b c d e f g h i j k l m n o p Blaesse P, Airaksinen MS, Rivera C, Kaila K (March 2009). "Cation-chloride cotransporters and neuronal function". Neuron 61 (6): 820–38. doi:10.1016/j.neuron.2009.03.003. PMID 19323993. 
  5. ^ a b c d e Vinay L, Jean-Xavier C (January 2008). "Plasticity of spinal cord locomotor networks and contribution of cation-chloride cotransporters". Brain Res Rev 57 (1): 103–10. doi:10.1016/j.brainresrev.2007.09.003. PMID 17949820. 
  6. ^ a b c d e Ginsberg MD (September 2008). "Neuroprotection for ischemic stroke: past, present and future". Neuropharmacology 55 (3): 363–89. doi:10.1016/j.neuropharm.2007.12.007. PMC 2631228. PMID 18308347. 
  7. ^ Báldi R, Varga C, Tamás G (October 2010). "Differential distribution of KCC2 along the axo-somato-dendritic axis of hippocampal principal cells". Eur. J. Neurosci. 32 (8): 1319–25. doi:10.1111/j.1460-9568.2010.07361.x. PMID 20880357. 
  8. ^ Lee HH, Walker JA, Williams JR, Goodier RJ, Payne JA, Moss SJ (October 2007). "Direct protein kinase C-dependent phosphorylation regulates the cell surface stability and activity of the potassium chloride cotransporter KCC2". J. Biol. Chem. 282 (41): 29777–84. doi:10.1074/jbc.M705053200. PMID 17693402. 
  9. ^ a b Stil A, Jean-Xavier C, Liabeuf S, Brocard C, Delpire E, Vinay L, Viemari JC (April 2011). "Contribution of the potassium-chloride co-transporter KCC2 to the modulation of lumbar spinal networks in mice". Eur. J. Neurosci. 33 (7): 1212–22. doi:10.1111/j.1460-9568.2010.07592.x. PMID 21255132. 
  10. ^ a b Uvarov P, Ludwig A, Markkanen M, Soni S, Hübner CA, Rivera C, Airaksinen MS (May 2009). "Coexpression and heteromerization of two neuronal K-Cl cotransporter isoforms in neonatal brain". J. Biol. Chem. 284 (20): 13696–704. doi:10.1074/jbc.M807366200. PMC 2679471. PMID 19307176. 
  11. ^ a b Blaesse P, Guillemin I, Schindler J, Schweizer M, Delpire E, Khiroug L, Friauf E, Nothwang HG (October 2006). "Oligomerization of KCC2 correlates with development of inhibitory neurotransmission". J. Neurosci. 26 (41): 10407–19. doi:10.1523/JNEUROSCI.3257-06.2006. PMID 17035525. 
  12. ^ a b Stil A, Liabeuf S, Jean-Xavier C, Brocard C, Viemari JC, Vinay L (December 2009). "Developmental up-regulation of the potassium-chloride cotransporter type 2 in the rat lumbar spinal cord". Neuroscience 164 (2): 809–21. doi:10.1016/j.neuroscience.2009.08.035. PMID 19699273. 
  13. ^ a b Rivera C, Li H, Thomas-Crusells J, Lahtinen H, Viitanen T, Nanobashvili A, Kokaia Z, Airaksinen MS, Voipio J, Kaila K, Saarma M (December 2002). "BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion". J. Cell Biol. 159 (5): 747–52. doi:10.1083/jcb.200209011. PMC 2173387. PMID 12473684. 
  14. ^ a b Rivera C, Voipio J, Thomas-Crusells J, Li H, Emri Z, Sipilä S, Payne JA, Minichiello L, Saarma M, Kaila K (May 2004). "Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2". J. Neurosci. 24 (19): 4683–91. doi:10.1523/JNEUROSCI.5265-03.2004. PMID 15140939. 
  15. ^ a b Kovalchuk Y, Holthoff K, Konnerth A (October 2004). "Neurotrophin action on a rapid timescale". Curr. Opin. Neurobiol. 14 (5): 558–63. doi:10.1016/j.conb.2004.08.014. PMID 15464888. 
  16. ^ a b Lee HH, Deeb TZ, Walker JA, Davies PA, Moss SJ (May 2011). "NMDA receptor activity downregulates KCC2 resulting in depolarizing GABA(A) receptor-mediated currents". Nat Neurosci 14 (6): 736–43. doi:10.1038/nn.2806. PMC 3102766. PMID 21532577. 

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