Chloride potassium symporter 5

{{short description|Protein found in humans}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox_gene}} '''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.<ref name="Entrez">{{cite web | title = Entrez Gene: SLC12A5 solute carrier family 12, (potassium-chloride transporter) member 5| url = https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=57468}}</ref> It is a critical mediator of synaptic inhibition, cellular protection against excitotoxicity<ref name="Watanabe_2009">{{cite journal | vauthors = Watanabe M, Wake H, Moorhouse AJ, Nabekura J | title = Clustering of neuronal K⁺-Cl⁻ cotransporters in lipid rafts by tyrosine phosphorylation | journal = The Journal of Biological Chemistry | volume = 284 | issue = 41 | pages = 27980–27988 | date = October 2009 | pmid = 19679663 | pmc = 2788850 | doi = 10.1074/jbc.M109.043620 | doi-access = free }}</ref><ref name="Gulyas_2001">{{cite journal | vauthors = Gulyás AI, Sík A, Payne JA, Kaila K, Freund TF | title = The KCl cotransporter, KCC2, is highly expressed in the vicinity of excitatory synapses in the rat hippocampus | journal = The European Journal of Neuroscience | volume = 13 | issue = 12 | pages = 2205–2217 | date = June 2001 | pmid = 11454023 | doi = 10.1046/j.0953-816x.2001.01600.x | s2cid = 22312687 | doi-access = free }}</ref> and may also act as a modulator of neuroplasticity.<ref name="Blaesse_2009">{{cite journal | vauthors = Blaesse P, Airaksinen MS, Rivera C, Kaila K | title = Cation-chloride cotransporters and neuronal function | journal = Neuron | volume = 61 | issue = 6 | pages = 820–838 | date = March 2009 | pmid = 19323993 | doi = 10.1016/j.neuron.2009.03.003 | s2cid = 10181096 | doi-access = free }}</ref><ref name="Gauvain_2011">{{cite journal | vauthors = Gauvain G, Chamma I, Chevy Q, Cabezas C, Irinopoulou T, Bodrug N, Carnaud M, Lévi S, Poncer JC | title = The neuronal K-Cl cotransporter KCC2 influences postsynaptic AMPA receptor content and lateral diffusion in dendritic spines | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 37 | pages = 15474–15479 | date = September 2011 | pmid = 21878564 | pmc = 3174661 | doi = 10.1073/pnas.1107893108 | doi-access = free | bibcode = 2011PNAS..10815474G }}</ref><ref name="Vinay_2007">{{cite journal | vauthors = Vinay L, Jean-Xavier C | title = Plasticity of spinal cord locomotor networks and contribution of cation-chloride cotransporters | journal = Brain Research Reviews | volume = 57 | issue = 1 | pages = 103–110 | date = January 2008 | pmid = 17949820 | doi = 10.1016/j.brainresrev.2007.09.003 | s2cid = 30698999 }}</ref><ref name="Ginsberg_2008">{{cite journal | vauthors = Ginsberg MD | title = Neuroprotection for ischemic stroke: past, present and future | journal = Neuropharmacology | volume = 55 | issue = 3 | pages = 363–389 | date = September 2008 | pmid = 18308347 | pmc = 2631228 | doi = 10.1016/j.neuropharm.2007.12.007 }}</ref> 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.<ref name="Entrez"/>

Animals with reduced expression of this transporter exhibit severe motor deficits, epileptiform activity, and spasticity.<ref name="Blaesse_2009"/> KCC2 knockout animals, in which KCC2 is completely absent, die postnatally due to respiratory failure.<ref name="Blaesse_2009"/>

==Location==

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.<ref name="Vinay_2007"/>

At the subcellular level, KCC2 has been found in membranes of the somata and dendrites of neurons,<ref name=Blaesse_2009 /><ref name="Baldi_2010">{{cite journal | vauthors = Báldi R, Varga C, Tamás G | title = Differential distribution of KCC2 along the axo-somato-dendritic axis of hippocampal principal cells | journal = The European Journal of Neuroscience | volume = 32 | issue = 8 | pages = 1319–1325 | date = October 2010 | pmid = 20880357 | doi = 10.1111/j.1460-9568.2010.07361.x | s2cid = 11676308 }}</ref> with no evidence of expression on axons.<ref name="Blaesse_2009"/> KCC2 has also been shown to colocalize with GABA_A receptors, which serve as ligand-gated ion channels to allow chloride ion movement across the cell membrane. Under normal conditions, the opening of GABA_A receptors permits the hyperpolarizing influx of chloride ions to inhibit postsynaptic neurons from firing.<ref name="Gulyas_2001"/>

Counterintuitively, KCC2 has also been shown to colocalize at excitatory synapses.<ref name="Watanabe_2009"/> One suggested explanation for such colocalization is a potential protective role of KCC2 against excitotoxicity.<ref name="Watanabe_2009"/><ref name="Gulyas_2001"/> 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.

== Structure ==

KCC2 is a member of the '''cation-chloride cotransporter (CCC)''' superfamily of proteins.<ref name="Lee_2007">{{cite journal | vauthors = Lee HH, Walker JA, Williams JR, Goodier RJ, Payne JA, Moss SJ | title = Direct protein kinase C-dependent phosphorylation regulates the cell surface stability and activity of the potassium chloride cotransporter KCC2 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 41 | pages = 29777–29784 | date = October 2007 | pmid = 17693402 | doi = 10.1074/jbc.M705053200 | doi-access = free }}</ref>

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.<ref name="Blaesse_2009"/><ref name="Stil_2011">{{cite journal | vauthors = Stil A, Jean-Xavier C, Liabeuf S, Brocard C, Delpire E, Vinay L, Viemari JC | title = Contribution of the potassium-chloride co-transporter KCC2 to the modulation of lumbar spinal networks in mice | journal = The European Journal of Neuroscience | volume = 33 | issue = 7 | pages = 1212–1222 | date = April 2011 | pmid = 21255132 | doi = 10.1111/j.1460-9568.2010.07592.x | s2cid = 9309418 }}</ref> The two isoforms arise from alternative promoters on the ''SLC12A5'' gene and differential splicing of the first mRNA exon.<ref name="Blaesse_2009"/><ref name="Stil_2011"/> The isoforms differ in their N-termini, with the KCC2a form constituting the larger of the two splice variants.<ref name="Uvarov_2009">{{cite journal | vauthors = Uvarov P, Ludwig A, Markkanen M, Soni S, Hübner CA, Rivera C, Airaksinen MS | title = Coexpression and heteromerization of two neuronal K-Cl cotransporter isoforms in neonatal brain | journal = The Journal of Biological Chemistry | volume = 284 | issue = 20 | pages = 13696–13704 | date = May 2009 | pmid = 19307176 | pmc = 2679471 | doi = 10.1074/jbc.M807366200 | doi-access = free }}</ref>

KCC2a levels remain relatively constant during pre- and postnatal development.<ref name="Uvarov_2009"/>

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.<ref name="Blaesse_2009"/>

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.<ref name="Blaesse_2009"/> Complete KCC2 knockouts (both KCC2a and KCC2b absent) die after birth due to respiratory failure.<ref name="Blaesse_2009"/>

===Oligomerization===

Both KCC2 isoforms can form homomultimers, or heteromultimers with other K-Cl symporters on the cell membrane to maintain chloride homeostasis in neurons.<ref name=Entrez /> Dimers, trimers, and tetramers involving KCC2 have been identified in brainstem neurons.<ref name="Blaesse_2006">{{cite journal | vauthors = Blaesse P, Guillemin I, Schindler J, Schweizer M, Delpire E, Khiroug L, Friauf E, Nothwang HG | title = Oligomerization of KCC2 correlates with development of inhibitory neurotransmission | journal = The Journal of Neuroscience | volume = 26 | issue = 41 | pages = 10407–10419 | date = October 2006 | pmid = 17035525 | pmc = 6674702 | doi = 10.1523/JNEUROSCI.3257-06.2006 | doi-access = free }}</ref> 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.<ref name="Blaesse_2006"/>

==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.<ref name="Stil_2009">{{cite journal | vauthors = Stil A, Liabeuf S, Jean-Xavier C, Brocard C, Viemari JC, Vinay L | title = Developmental up-regulation of the potassium-chloride cotransporter type 2 in the rat lumbar spinal cord | journal = Neuroscience | volume = 164 | issue = 2 | pages = 809–821 | date = December 2009 | pmid = 19699273 | doi = 10.1016/j.neuroscience.2009.08.035 | s2cid = 41738829 }}</ref> Thus, during embryonic development, the chloride gradient is such that stimulation of GABA_A receptors and glycine receptors at inhibitory synapses causes chloride ions to flow out of cells, making the internal neuronal environment less negative (i.e. more depolarized) than it would be at rest. At this stage, GABA_A receptors and glycine receptors act as excitatory rather than inhibitory effectors on postsynaptic neurons, resulting in depolarization and hyperexcitability of neural networks.<ref name="Blaesse_2009"/><ref name="Vinay_2007"/><ref name="Ginsberg_2008"/>

During postnatal development, KCC2 levels are strongly upregulated while NKCC1 levels are down regulated.<ref name="Stil_2009"/> 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 GABA_A receptor and glycine receptor stimulation causes chloride ion influx, making the internal neuronal environment more negative (i.e. 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.

== Function ==

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

# Establishing the chloride ion gradient necessary for postsynaptic inhibition # Protecting neuronal networks against stimulation-induced excitotoxicity # Contributing to dendritic spine morphogenesis and glutamatergic synaptic function

=== Postsynaptic inhibition ===

Reduced expression or functional impairment of KCC2 leads to elevated intracellular chloride levels, which weaken inhibitory GABAergic signalling and increase neuronal excitability, particularly in hippocampal circuits.

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 GABA_A 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.<ref name="Blaesse_2009" /> In fact, any disruption of the neuronal K⁺ gradient would indirectly affect KCC2 activity.

Loss of KCC2 following neuronal damage (i.e. 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<ref name="Vinay_2007"/> as GABA_A 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.<ref name="Watanabe_2009"/> 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.<ref name="Watanabe_2009"/>

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.<ref name="Watanabe_2009"/><ref name="Gulyas_2001"/>

=== Morphogenesis and function of glutamatergic synapses ===

In addition to controlling the efficacy of GABAergic synapses through chloride homeostasis, KCC2 play a critical role in the morphogenesis and function of glutamatergic synapses within the central nervous system. Studies on hippocampal tissue in KCC2 knockout animals showed that neurons lacking KCC2 have stunted dendritic growth and malformed dendritic spines.<ref name=Blaesse_2009 /> Recent studies demonstrate that KCC2 plays a critical role in the structure and function of dendritic spines<ref name="Gauvain_2011"/> which host most excitatory synapses in cortical neurons. Through an interaction with actin cytoskeleton, KCC2 forms a molecular barrier to the diffusion of transmembrane proteins within dendritic spines, thereby regulating the local confinement of AMPA receptors and synaptic potency.<ref name="Gauvain_2011"/>

It has been proposed that the downregulation of KCC2 observed following neuronal trauma, and the consequent depolarizing shift of GABA_A-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 surviving neurons to compensate for damage in the network.<ref name="Blaesse_2009"/><ref name="Vinay_2007"/><ref name="Ginsberg_2008"/> In addition, reduced glutamatergic transmission upon KCC2 downregulation may serve as a homeostatic process to compensate for the reduced GABA transmission due to altered chloride extrusion.<ref name="Gauvain_2011"/>

===Oncogenesis=== Mutations in SLC12A5 are associated with colon cancer.<ref>{{cite journal | vauthors = Yu C, Yu J, Yao X, Wu WK, Lu Y, Tang S, Li X, Bao L, Li X, Hou Y, Wu R, Jian M, Chen R, Zhang F, Xu L, Fan F, He J, Liang Q, Wang H, Hu X, He M, Zhang X, Zheng H, Li Q, Wu H, Chen Y, Yang X, Zhu S, Xu X, Yang H, Wang J, Zhang X, Sung JJ, Li Y, Wang J | title = Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing | journal = Cell Research | volume = 24 | issue = 6 | pages = 701–712 | date = June 2014 | pmid = 24699064 | pmc = 4042168 | doi = 10.1038/cr.2014.43 }}</ref>

==Regulation==

=== 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).<ref name="Riviera_2002">{{cite journal | vauthors = Rivera C, Li H, Thomas-Crusells J, Lahtinen H, Viitanen T, Nanobashvili A, Kokaia Z, Airaksinen MS, Voipio J, Kaila K, Saarma M | title = BDNF-induced TrkB activation down-regulates the K+-Cl- cotransporter KCC2 and impairs neuronal Cl- extrusion | journal = The Journal of Cell Biology | volume = 159 | issue = 5 | pages = 747–752 | date = December 2002 | pmid = 12473684 | pmc = 2173387 | doi = 10.1083/jcb.200209011 }}</ref><ref name="Riviera_2004">{{cite journal | vauthors = Rivera C, Voipio J, Thomas-Crusells J, Li H, Emri Z, Sipilä S, Payne JA, Minichiello L, Saarma M, Kaila K | title = Mechanism of activity-dependent downregulation of the neuron-specific K-Cl cotransporter KCC2 | journal = The Journal of Neuroscience | volume = 24 | issue = 19 | pages = 4683–4691 | date = May 2004 | pmid = 15140939 | pmc = 6729393 | doi = 10.1523/JNEUROSCI.5265-03.2004 | doi-access = free }}</ref><ref name="Kovalchuk_2004">{{cite journal | vauthors = Kovalchuk Y, Holthoff K, Konnerth A | title = Neurotrophin action on a rapid timescale | journal = Current Opinion in Neurobiology | volume = 14 | issue = 5 | pages = 558–563 | date = October 2004 | pmid = 15464888 | doi = 10.1016/j.conb.2004.08.014 | s2cid = 41037789 }}</ref>

=== 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 (i.e. TrkB) phosphorylation downregulates KCC2 activity.<ref name="Riviera_2002"/><ref name="Riviera_2004"/><ref name="Kovalchuk_2004"/><ref name="Lee_2011">{{cite journal | vauthors = Lee HH, Deeb TZ, Walker JA, Davies PA, Moss SJ | title = NMDA receptor activity downregulates KCC2 resulting in depolarizing GABAA receptor-mediated currents | journal = Nature Neuroscience | volume = 14 | issue = 6 | pages = 736–743 | date = June 2011 | pmid = 21532577 | pmc = 3102766 | doi = 10.1038/nn.2806 }}</ref> *PKC phosphorylation of the C-terminus Ser940 residue of the KCC2 protein upregulates KCC2 activity by increasing surface stability.<ref name="Blaesse_2009"/> Conversely, Ser940 dephosphorylation leads to enhanced membrane diffusion and endocytosis of KCC2.<ref name="Chamma_2013">{{cite journal | vauthors = Chamma I, Heubl M, Chevy Q, Renner M, Moutkine I, Eugène E, Poncer JC, Lévi S | title = Activity-dependent regulation of the K/Cl transporter KCC2 membrane diffusion, clustering, and function in hippocampal neurons | journal = The Journal of Neuroscience | volume = 33 | issue = 39 | pages = 15488–15503 | date = September 2013 | pmid = 24068817 | pmc = 6618451 | doi = 10.1523/JNEUROSCI.5889-12.2013 | doi-access = free }}</ref> KCC2 has an extremely high rate of turnover at the plasmalemma (minutes),<ref name="Blaesse_2009"/> 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.<ref name="Ginsberg_2008"/><ref name="Lee_2011"/> This process involves rapid dephosphorylation on Ser940 and calpain protease cleavage of KCC2, leading to enhanced membrane diffusion and endocytosis of the transporter,<ref name="Chamma_2013"/> as demonstrated in experiments using single particle tracking.

Glutamate release occurs not only at excitatory synapses, but is also known to occur after neuronal damage or ischemic insult.<ref name="Ginsberg_2008"/> Thus, activity-dependent downregulation may be the underlying mechanism by which KCC2 downregulation occurs following central nervous system injury.

== See also == * Solute carrier family

== References == {{reflist|2}}

== Further reading == {{refbegin | 2}} * {{cite journal | vauthors = Chevy Q, Heubl M, Goutierre M, Backer S, Moutkine I, Eugène E, Bloch-Gallego E, Lévi S, Poncer JC | title = KCC2 Gates Activity-Driven AMPA Receptor Traffic through Cofilin Phosphorylation | journal = The Journal of Neuroscience | volume = 35 | issue = 48 | pages = 15772–15786 | date = December 2015 | pmid = 26631461 | pmc = 6605455 | doi = 10.1523/JNEUROSCI.1735-15.2015 | doi-access = free }} * {{cite journal | vauthors = Chamma I, Chevy Q, Poncer JC, Lévi S | title = Role of the neuronal K-Cl co-transporter KCC2 in inhibitory and excitatory neurotransmission | journal = Frontiers in Cellular Neuroscience | volume = 6 | pages = 5 | year = 2015 | pmid = 22363264 | pmc = 3282916 | doi = 10.3389/fncel.2012.00005 | doi-access = free }} * {{cite journal | vauthors = Hebert SC, Mount DB, Gamba G | title = Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family | journal = Pflügers Archiv | volume = 447 | issue = 5 | pages = 580–593 | date = February 2004 | pmid = 12739168 | doi = 10.1007/s00424-003-1066-3 | s2cid = 21998913 }} * {{cite journal | vauthors = Rivera C, Voipio J, Kaila K | title = Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII | journal = The Journal of Physiology | volume = 562 | issue = Pt 1 | pages = 27–36 | date = January 2005 | pmid = 15528236 | pmc = 1665491 | doi = 10.1113/jphysiol.2004.077495 }} * {{cite journal | vauthors = Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA | title = A "double adaptor" method for improved shotgun library construction | journal = Analytical Biochemistry | volume = 236 | issue = 1 | pages = 107–113 | date = April 1996 | pmid = 8619474 | doi = 10.1006/abio.1996.0138 }} * {{cite journal | vauthors = Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA | title = Large-scale concatenation cDNA sequencing | journal = Genome Research | volume = 7 | issue = 4 | pages = 353–358 | date = April 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }} * {{cite journal | vauthors = Hirosawa M, Nagase T, Ishikawa K, Kikuno R, Nomura N, Ohara O | title = Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain | journal = DNA Research | volume = 6 | issue = 5 | pages = 329–336 | date = October 1999 | pmid = 10574461 | doi = 10.1093/dnares/6.5.329 | doi-access = free }} * {{cite journal | vauthors = Hübner CA, Stein V, Hermans-Borgmeyer I, Meyer T, Ballanyi K, Jentsch TJ | title = Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition | journal = Neuron | volume = 30 | issue = 2 | pages = 515–524 | date = May 2001 | pmid = 11395011 | doi = 10.1016/S0896-6273(01)00297-5 | s2cid = 4971832 | citeseerx = 10.1.1.476.2965 }} * {{cite journal | vauthors = Sallinen R, Tornberg J, Putkiranta M, Horelli-Kuitunen N, Airaksinen MS, Wessman M | title = 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 | journal = Cytogenetics and Cell Genetics | volume = 94 | issue = 1–2 | pages = 67–70 | year = 2001 | pmid = 11701957 | doi = 10.1159/000048785 | s2cid = 33299788 }} * {{cite journal | vauthors = Song L, Mercado A, Vázquez N, Xie Q, Desai R, George AL, Gamba G, Mount DB | title = Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter | journal = Brain Research. Molecular Brain Research | volume = 103 | issue = 1–2 | pages = 91–105 | date = June 2002 | pmid = 12106695 | doi = 10.1016/S0169-328X(02)00190-0 }} * {{cite journal | vauthors = Bräuer M, Frei E, Claes L, Grissmer S, Jäger H | title = Influence of K-Cl cotransporter activity on activation of volume-sensitive Cl- channels in human osteoblasts | journal = American Journal of Physiology. Cell Physiology | volume = 285 | issue = 1 | pages = C22–C30 | date = July 2003 | pmid = 12637262 | doi = 10.1152/ajpcell.00289.2002 | doi-access = }} * {{cite journal | vauthors = Lee H, Chen CX, Liu YJ, Aizenman E, Kandler K | title = KCC2 expression in immature rat cortical neurons is sufficient to switch the polarity of GABA responses | journal = The European Journal of Neuroscience | volume = 21 | issue = 9 | pages = 2593–2599 | date = May 2005 | pmid = 15932617 | pmc = 2945502 | doi = 10.1111/j.1460-9568.2005.04084.x }} * {{cite journal | vauthors = Mercado A, Broumand V, Zandi-Nejad K, Enck AH, Mount DB | title = A C-terminal domain in KCC2 confers constitutive K+-Cl- cotransport | journal = The Journal of Biological Chemistry | volume = 281 | issue = 2 | pages = 1016–1026 | date = January 2006 | pmid = 16291749 | doi = 10.1074/jbc.M509972200 | doi-access = free }} * {{cite journal | vauthors = Vanhatalo S, Palva JM, Andersson S, Rivera C, Voipio J, Kaila K | title = Slow endogenous activity transients and developmental expression of K+-Cl- cotransporter 2 in the immature human cortex | journal = The European Journal of Neuroscience | volume = 22 | issue = 11 | pages = 2799–2804 | date = December 2005 | pmid = 16324114 | doi = 10.1111/j.1460-9568.2005.04459.x | s2cid = 37264065 }} * {{cite journal | vauthors = Lee HH, Walker JA, Williams JR, Goodier RJ, Payne JA, Moss SJ | title = Direct protein kinase C-dependent phosphorylation regulates the cell surface stability and activity of the potassium chloride cotransporter KCC2 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 41 | pages = 29777–29784 | date = October 2007 | pmid = 17693402 | doi = 10.1074/jbc.M705053200 | doi-access = free }} * {{cite journal | vauthors = Uvarov P, Ludwig A, Markkanen M, Pruunsild P, Kaila K, Delpire E, Timmusk T, Rivera C, Airaksinen MS | title = A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2 | journal = The Journal of Biological Chemistry | volume = 282 | issue = 42 | pages = 30570–30576 | date = October 2007 | pmid = 17715129 | doi = 10.1074/jbc.M705095200 | doi-access = free }} {{refend}}

== External links == * [http://www.medicalnewstoday.com/articles/54540.php How Brain Injury Leads To Seizures, Memory Problems] {{Webarchive|url=https://web.archive.org/web/20081206150443/http://www.medicalnewstoday.com/articles/54540.php |date=2008-12-06 }} - medical news, 20 Oct 2006.

{{NLM content}} {{Membrane transport proteins}} {{ion pumps}}

Category:Solute carrier family