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{{Infobox_gene}}
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'''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/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57468| accessdate = }}</ref> It is a critical mediator of [[inhibitory postsynaptic potential|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<sup>+</sup>-Cl<sup>−</sup> cotransporters in lipid rafts by tyrosine phosphorylation | journal = J. Biol. Chem. | volume = 284 | issue = 41 | pages = 27980–8 |date=October 2009 | pmid = 19679663 | pmc = 2788850 | doi = 10.1074/jbc.M109.043620 }}</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 = Eur. J. Neurosci. | volume = 13 | issue = 12 | pages = 2205–17 |date=June 2001 | pmid = 11454023 | doi = 10.1046/j.0953-816x.2001.01600.x| url = }}</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 = 820–38 |date=March 2009 | pmid = 19323993 | doi = 10.1016/j.neuron.2009.03.003 | url = }}</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 = Proc. Natl. Acad. Sci. U.S.A. | volume = 108 | issue = 37 | pages = 15474–9 |date=September 2011 | pmid = 21878564 | pmc = 3174661 | doi = 10.1073/pnas.1107893108 }}</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 Res Rev | volume = 57 | issue = 1 | pages = 103–10 |date=January 2008 | pmid = 17949820 | doi = 10.1016/j.brainresrev.2007.09.003 }}</ref><ref name="Ginsberg_2008">{{cite journal | author = Ginsberg MD | title = Neuroprotection for ischemic stroke: past, present and future | journal = Neuropharmacology | volume = 55 | issue = 3 | pages = 363–89 |date=September 2008 | pmid = 18308347 | pmc = 2631228 | doi = 10.1016/j.neuropharm.2007.12.007 | url = }}</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"/>
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
Animals with reduced expression of this transporter exhibit severe motor deficits, [[epileptiform]] activity, and spasticity.<ref name="Blaesse_2009"/> KCC2 [[knockout mouse|knockout animals]], in which KCC2 is completely absent, die postnatally due to respiratory failure.<ref name="Blaesse_2009"/>
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Solute carrier family 12, (potassium-chloride transporter) member 5
| HGNCid = 13818
| Symbol = SLC12A5
| AltSymbols =; KCC2; KIAA1176
| OMIM = 606726
| ECnumber = 
| Homologene = 10665
| MGIid = 1862037
| GeneAtlas_image1 = PBB_GE_SLC12A5_210040_at_tn.png
| Function = {{GNF_GO|id=GO:0005215 |text = transporter activity}} {{GNF_GO|id=GO:0015293 |text = symporter activity}} {{GNF_GO|id=GO:0015379 |text = potassium:chloride symporter activity}} {{GNF_GO|id=GO:0030955 |text = potassium ion binding}}
| Component = {{GNF_GO|id=GO:0005886 |text = plasma membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006811 |text = ion transport}} {{GNF_GO|id=GO:0006813 |text = potassium ion transport}} {{GNF_GO|id=GO:0006814 |text = sodium ion transport}} {{GNF_GO|id=GO:0006821 |text = chloride transport}} {{GNF_GO|id=GO:0006873 |text = cell ion homeostasis}} {{GNF_GO|id=GO:0007268 |text = synaptic transmission}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 57468
    | Hs_Ensembl = ENSG00000124140
    | Hs_RefseqProtein = NP_065759
    | Hs_RefseqmRNA = NM_020708
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 20
    | Hs_GenLoc_start = 44091242
    | Hs_GenLoc_end = 44122196
    | Hs_Uniprot = Q9H2X9
    | Mm_EntrezGene = 57138
    | Mm_Ensembl = ENSMUSG00000017740
    | Mm_RefseqmRNA = NM_020333
    | Mm_RefseqProtein = NP_065066
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 2
    | Mm_GenLoc_start = 164659459
    | Mm_GenLoc_end = 164690936
    | Mm_Uniprot = Q3UHQ2
  }}
}}
'''potassium-chloride transporter member 5''' is a type of [[chloride potassium symporter]].


This potassium-chloride transporter is an integral membrane K-Cl cotransporter that can function in either a net efflux or influx pathway, depending on the chemical concentration gradients of potassium and chloride. The encoded protein can act as a homomultimer, or as a heteromultimer with other K-Cl cotransporters, to maintain chloride homeostasis in neurons.<ref name="entrez">{{cite web | title = Entrez Gene: SLC12A5 solute carrier family 12, (potassium-chloride transporter) member 5| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57468| accessdate = }}</ref>
==Location==


It is encoded by the gene '''SLC12A5''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: SLC12A5 solute carrier family 12, (potassium-chloride transporter) member 5| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=57468| accessdate = }}</ref>
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 = Eur. J. Neurosci. | volume = 32 | issue = 8 | pages = 1319–25 |date=October 2010 | pmid = 20880357 | doi = 10.1111/j.1460-9568.2010.07361.x | url = }}</ref> with no evidence of expression on [[axons]].<ref name="Blaesse_2009"/> KCC2 has also been shown to colocalize with [[GABA receptors|GABA<sub>A</sub> receptors]], which serve as ligand-gated ion channels to allow chloride ion movement across the cell membrane. Under normal conditions, the opening of GABA<sub>A</sub> 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 pressure|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 = J. Biol. Chem. | volume = 282 | issue = 41 | pages = 29777–84 |date=October 2007 | pmid = 17693402 | doi = 10.1074/jbc.M705053200 | url = }}</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 = Eur. J. Neurosci. | volume = 33 | issue = 7 | pages = 1212–22 |date=April 2011 | pmid = 21255132 | doi = 10.1111/j.1460-9568.2010.07592.x }}</ref> The two isoforms arise from alternative [[promoter (biology)|promoters]] on the ''SLC12A5'' gene and [[RNA splicing|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 = J. Biol. Chem. | volume = 284 | issue = 20 | pages = 13696–704 |date=May 2009 | pmid = 19307176 | pmc = 2679471 | doi = 10.1074/jbc.M807366200 }}</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 = J. Neurosci. | volume = 26 | issue = 41 | pages = 10407–19 |date=October 2006 | pmid = 17035525 | doi = 10.1523/JNEUROSCI.3257-06.2006 | url = }}</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<sup>+</sup>/K<sup>+</sup> 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 = 809–21 |date=December 2009 | pmid = 19699273 | doi = 10.1016/j.neuroscience.2009.08.035 | url = }}</ref> Thus, during embryonic development, the chloride gradient is such that stimulation of GABA<sub>A</sub> 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 [[depolarization|depolarized]]) than it would be at rest. At this stage, GABA<sub>A</sub> 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<sub>A</sub> receptor and glycine receptor stimulation causes chloride ion influx, making the internal neuronal environment more negative (i.e. more [[hyperpolarization (biology)|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 from against stimulation-induced excitotoxicity
# Contributing to dendritic spine morphogenesis and glutamatergic synaptic function
 
=== Postsynaptic inhibition ===
 
KCC2 is a potassium (K<sup>+</sup>)/chloride (Cl<sup>−</sup>) symporter that maintains chloride homeostasis in neurons. The electrochemical chloride gradient established by KCC2 activity is crucial for classical postsynaptic inhibition through GABA<sub>A</sub> receptors and glycine receptors in the central nervous system.  KCC2 utilizes the potassium gradient generated by the [[sodium potassium pump|Na<sup>+</sup>/K<sup>+</sup> pump]] to drive chloride extrusion from neurons.<ref name="Blaesse_2009"/> In fact, any disruption of the neuronal K<sup>+</sup> 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<sub>A</sub> 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 [[hippocampus|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 confinment 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<sub>A</sub>-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.<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 {{SWL|type=mutation_results_in|target=colon cancer|label=colon cancer}}.<ref>{{Cite journal
| pmid = 24699064
| year = 2014
| author1 = Yu
| first1 = C
| title = Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing
| journal = Cell Research
| last2 = Yu
| first2 = J
| last3 = Yao
| first3 = X
| last4 = Wu
| first4 = W. K.
| last5 = Lu
| first5 = Y
| last6 = Tang
| first6 = S
| last7 = Li
| first7 = X
| last8 = Bao
| first8 = L
| last9 = Li
| first9 = X
| last10 = Hou
| first10 = Y
| last11 = Wu
| first11 = R
| last12 = Jian
| first12 = M
| last13 = Chen
| first13 = R
| last14 = Zhang
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| last15 = Xu
| first15 = L
| last16 = Fan
| first16 = F
| last17 = He
| first17 = J
| last18 = Liang
| first18 = Q
| last19 = Wang
| first19 = H
| last20 = Hu
| first20 = X
| last21 = He
| first21 = M
| last22 = Zhang
| first22 = X
| last23 = Zheng
| first23 = H
| last24 = Li
| first24 = Q
| last25 = Wu
| first25 = H
| last26 = Chen
| first26 = Y
| last27 = Yang
| first27 = X
| last28 = Zhu
| first28 = S
| last29 = Xu
| first29 = X
| last30 = Yang
| first30 = H
| display-authors = 29
| doi = 10.1038/cr.2014.43
| volume=24
| issue=6
| pages=701–12
}}</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 [[Neurotrophin-4|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<sup>+</sup>-Cl<sup>−</sup> cotransporter KCC2 and impairs neuronal Cl<sup>−</sup> extrusion | journal = J. Cell Biol. | volume = 159 | issue = 5 | pages = 747–52 |date=December 2002 | pmid = 12473684 | pmc = 2173387 | doi = 10.1083/jcb.200209011 | url = }}</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 = J. Neurosci. | volume = 24 | issue = 19 | pages = 4683–91 |date=May 2004 | pmid = 15140939 | doi = 10.1523/JNEUROSCI.5265-03.2004 | url = }}</ref><ref name="Kovalchuk_2004">{{cite journal |vauthors=Kovalchuk Y, Holthoff K, Konnerth A | title = Neurotrophin action on a rapid timescale | journal = Curr. Opin. Neurobiol. | volume = 14 | issue = 5 | pages = 558–63 |date=October 2004 | pmid = 15464888 | doi = 10.1016/j.conb.2004.08.014 | url = }}</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|Wnk1]]/[[WNK3|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 GABA(A) receptor-mediated currents | journal = Nat Neurosci | volume = 14| issue = 6| pages = 736–43|date=May 2011 | pmid = 21532577 | doi = 10.1038/nn.2806 | url = | pmc = 3102766 }}</ref>
*[[Protein kinase C|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 = J. Neurosci. | volume = 33 | issue = 39 | pages = 15488–503 |date=September 2013 | pmid = 24068817 | doi = 10.1523/JNEUROSCI.5889-12.2013 }}</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 Ca<sup>2+</sup> 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==
==See also==
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==Further reading==
==Further reading==
{{refbegin | 2}}
{{refbegin | 2}}
{{PBB_Further_reading
* {{cite journal  |vauthors=Chamma I, Chevy Q, Poncer JC, Levi S |title=Role of the neuronal K-Cl co-transporter KCC2 in inhibitory and excitatory neurotransmission. |journal=Front Cell Neurosci |volume=6 |pages= 5 |year= 2013 |pmid= 22363264 |doi= 10.3389/fncel.2012.00005  | pmc=3282916 }}
| citations =  
* {{cite journal  |vauthors=Hebert SC, Mount DB, Gamba G |title=Molecular physiology of cation-coupled Cl<sup>−</sup> cotransport: the SLC12 family |journal=Pflugers Arch. |volume=447 |issue= 5 |pages= 580–93 |year= 2004 |pmid= 12739168 |doi= 10.1007/s00424-003-1066-3 }}
*{{cite journal  | author=Hebert SC, Mount DB, Gamba G |title=Molecular physiology of cation-coupled Cl- cotransport: the SLC12 family. |journal=Pflugers Arch. |volume=447 |issue= 5 |pages= 580-93 |year= 2004 |pmid= 12739168 |doi= 10.1007/s00424-003-1066-3 }}
* {{cite journal  |vauthors=Rivera C, Voipio J, Kaila K |title=Two developmental switches in GABAergic signalling: the K<sup>+</sup>-Cl<sup>−</sup> cotransporter KCC2 and carbonic anhydrase CAVII |journal=J. Physiol. |volume=562 |issue= Pt 1 |pages= 27–36 |year= 2005 |pmid= 15528236 |doi= 10.1113/jphysiol.2004.077495 | pmc=1665491 }}
*{{cite journal  | author=Rivera C, Voipio J, Kaila K |title=Two developmental switches in GABAergic signalling: the K+-Cl- cotransporter KCC2 and carbonic anhydrase CAVII. |journal=J. Physiol. (Lond.) |volume=562 |issue= Pt 1 |pages= 27-36 |year= 2005 |pmid= 15528236 |doi= 10.1113/jphysiol.2004.077495 }}
* {{cite journal  | author=Andersson B |title=A "double adaptor" method for improved shotgun library construction |journal=Anal. Biochem. |volume=236 |issue= 1 |pages= 107–13 |year= 1996 |pmid= 8619474 |doi= 10.1006/abio.1996.0138 |name-list-format=vanc| author2=Wentland MA  | author3=Ricafrente JY  | display-authors=3  | last4=Liu  | first4=W  | last5=Gibbs  | first5=RA }}
*{{cite journal  | author=Andersson B, Wentland MA, Ricafrente JY, ''et al.'' |title=A "double adaptor" method for improved shotgun library construction. |journal=Anal. Biochem. |volume=236 |issue= 1 |pages= 107-13 |year= 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 Res. | volume = 7 | issue = 4 | pages = 353–8 |date=April 1997 | pmid = 9110174 | pmc = 139146 | doi = 10.1101/gr.7.4.353 }}
*{{cite journal | author=Yu W, Andersson B, Worley KC, ''et al.'' |title=Large-scale concatenation cDNA sequencing. |journal=Genome Res. |volume=7 |issue= 4 |pages= 353-8 |year= 1997 |pmid= 9110174 |doi= }}
* {{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 Res. | volume = 6 | issue = 5 | pages = 329–36 |date=October 1999 | pmid = 10574461 | doi = 10.1093/dnares/6.5.329 }}
*{{cite journal | author=Hirosawa M, Nagase T, Ishikawa K, ''et al.'' |title=Characterization of cDNA clones selected by the GeneMark analysis from size-fractionated cDNA libraries from human brain. |journal=DNA Res. |volume=6 |issue= 5 |pages= 329-36 |year= 2000 |pmid= 10574461 |doi= }}
* {{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 = 515–24 |date=May 2001 | pmid = 11395011 | doi = 10.1016/S0896-6273(01)00297-5 }}
*{{cite journal | author=Hübner CA, Stein V, Hermans-Borgmeyer I, ''et al.'' |title=Disruption of KCC2 reveals an essential role of K-Cl cotransport already in early synaptic inhibition. |journal=Neuron |volume=30 |issue= 2 |pages= 515-24 |year= 2001 |pmid= 11395011 |doi= }}
* {{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 = Cytogenet. Cell Genet. | volume = 94 | issue = 1-2 | pages = 67–70 | year = 2001 | pmid = 11701957 | doi = 10.1159/000048785 }}
*{{cite journal | author=Sallinen R, Tornberg J, Putkiranta M, ''et al.'' |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=Cytogenet. Cell Genet. |volume=94 |issue= 1-2 |pages= 67-70 |year= 2001 |pmid= 11701957 |doi=  }}
* {{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 Res. Mol. Brain Res. | volume = 103 | issue = 1-2 | pages = 91–105 |date=June 2002 | pmid = 12106695 | doi = 10.1016/S0169-328X(02)00190-0 }}
*{{cite journal  | author=Deloukas P, Matthews LH, Ashurst J, ''et al.'' |title=The DNA sequence and comparative analysis of human chromosome 20. |journal=Nature |volume=414 |issue= 6866 |pages= 865-71 |year= 2002 |pmid= 11780052 |doi= 10.1038/414865a }}
* {{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 = Am. J. Physiol., Cell Physiol. | volume = 285 | issue = 1 | pages = C22–30 |date=July 2003 | pmid = 12637262 | doi = 10.1152/ajpcell.00289.2002 }}
*{{cite journal | author=Song L, Mercado A, Vázquez N, ''et al.'' |title=Molecular, functional, and genomic characterization of human KCC2, the neuronal K-Cl cotransporter. |journal=Brain Res. Mol. Brain Res. |volume=103 |issue= 1-2 |pages= 91-105 |year= 2002 |pmid= 12106695 |doi= }}
* {{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 = Eur. J. Neurosci. | volume = 21 | issue = 9 | pages = 2593–9 |date=May 2005 | pmid = 15932617 | pmc = 2945502 | doi = 10.1111/j.1460-9568.2005.04084.x }}
*{{cite journal  | author=Strausberg RL, Feingold EA, Grouse LH, ''et al.'' |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899-903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899 }}
* {{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 = J. Biol. Chem. | volume = 281 | issue = 2 | pages = 1016–26 |date=January 2006 | pmid = 16291749 | doi = 10.1074/jbc.M509972200 }}
*{{cite journal | author=Bräuer M, Frei E, Claes L, ''et al.'' |title=Influence of K-Cl cotransporter activity on activation of volume-sensitive Cl- channels in human osteoblasts. |journal=Am. J. Physiol., Cell Physiol. |volume=285 |issue= 1 |pages= C22-30 |year= 2003 |pmid= 12637262 |doi= 10.1152/ajpcell.00289.2002 }}
* {{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 = Eur. J. Neurosci. | volume = 22 | issue = 11 | pages = 2799–804 |date=December 2005 | pmid = 16324114 | doi = 10.1111/j.1460-9568.2005.04459.x }}
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
* {{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 = J. Biol. Chem. | volume = 282 | issue = 41 | pages = 29777–84 |date=October 2007 | pmid = 17693402 | doi = 10.1074/jbc.M705053200 }}
*{{cite journal  | author=Lee H, Chen CX, Liu YJ, ''et al.'' |title=KCC2 expression in immature rat cortical neurons is sufficient to switch the polarity of GABA responses. |journal=Eur. J. Neurosci. |volume=21 |issue= 9 |pages= 2593-9 |year= 2005 |pmid= 15932617 |doi= 10.1111/j.1460-9568.2005.04084.x }}
* {{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 = J. Biol. Chem. | volume = 282 | issue = 42 | pages = 30570–6 |date=October 2007 | pmid = 17715129 | doi = 10.1074/jbc.M705095200 }}
*{{cite journal | author=Mercado A, Broumand V, Zandi-Nejad K, ''et al.'' |title=A C-terminal domain in KCC2 confers constitutive K+-Cl- cotransport. |journal=J. Biol. Chem. |volume=281 |issue= 2 |pages= 1016-26 |year= 2006 |pmid= 16291749 |doi= 10.1074/jbc.M509972200 }}
*{{cite journal | author=Vanhatalo S, Palva JM, Andersson S, ''et al.'' |title=Slow endogenous activity transients and developmental expression of K+-Cl- cotransporter 2 in the immature human cortex. |journal=Eur. J. Neurosci. |volume=22 |issue= 11 |pages= 2799-804 |year= 2006 |pmid= 16324114 |doi= 10.1111/j.1460-9568.2005.04459.x }}
*{{cite journal | author=Lee HH, Walker JA, Williams JR, ''et al.'' |title=Direct protein kinase C-dependent phosphorylation regulates the cell surface stability and activity of the potassium chloride cotransporter KCC2. |journal=J. Biol. Chem. |volume=282 |issue= 41 |pages= 29777-84 |year= 2007 |pmid= 17693402 |doi= 10.1074/jbc.M705053200 }}
*{{cite journal | author=Uvarov P, Ludwig A, Markkanen M, ''et al.'' |title=A novel N-terminal isoform of the neuron-specific K-Cl cotransporter KCC2. |journal=J. Biol. Chem. |volume=282 |issue= 42 |pages= 30570-6 |year= 2007 |pmid= 17715129 |doi= 10.1074/jbc.M705095200 }}
}}
{{refend}}
{{refend}}


{{membrane-protein-stub}}
==External links==
* [http://www.medicalnewstoday.com/articles/54540.php How Brain Injury Leads To Seizures, Memory Problems] - medical news, 20 Oct 2006.
 
{{NLM content}}
{{NLM content}}
{{Membrane transport proteins}}
{{Membrane transport proteins}}
{{ion pumps}}
{{ion pumps}}
[[Category:Solute carrier family]]
[[Category:Solute carrier family]]

Revision as of 14:49, 26 November 2017

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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][7] 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]

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.[6]

At the subcellular level, KCC2 has been found in membranes of the somata and dendrites of neurons,[4][8] 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.

Structure

KCC2 is a member of the cation-chloride cotransporter (CCC) superfamily of proteins.[9]

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][10] The two isoforms arise from alternative promoters on the SLC12A5 gene and differential splicing of the first mRNA exon.[4][10] The isoforms differ in their N-termini, with the KCC2a form constituting the larger of the two splice variants.[11]

KCC2a levels remain relatively constant during pre- and postnatal development.[11]

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]

Oligomerization

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.[12] 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.[12]

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.[13] 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 (i.e. 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][6][7]

During postnatal development, KCC2 levels are strongly upregulated while NKCC1 levels are down regulated.[13] 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 (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:

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

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 (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[6] 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]

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.[4] Recent studies demonstrate that KCC2 plays a critical role in the structure and function of dendritic spines[5] 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 confinment of AMPA receptors and synaptic potency.[5]

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][6][7] 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.[5]

Oncogenesis

Mutations in SLC12A5 are associated with colon cancer .[14]

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).[15][16][17]

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.[15][16][17][18]
  • PKC phosphorylation of the C-terminus Ser940 residue of the KCC2 protein upregulates KCC2 activity by increasing surface stability.[4] Conversely, Ser940 dephosphorylation leads to enhanced membrane diffusion and endocytosis of KCC2.[19]

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.[7][18] This process involves rapid dephosphorylation on Ser940 and calpain protease cleavage of KCC2, leading to enhanced membrane diffusion and endocytosis of the transporter,[19] 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.[7] Thus, activity-dependent downregulation may be the underlying mechanism by which KCC2 downregulation occurs following central nervous system injury.

See also

References

  1. ↑ 1.0 1.1 1.2 "Entrez Gene: SLC12A5 solute carrier family 12, (potassium-chloride transporter) member 5".
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 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. ↑ 3.0 3.1 3.2 3.3 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. ↑ 4.00 4.01 4.02 4.03 4.04 4.05 4.06 4.07 4.08 4.09 4.10 4.11 4.12 4.13 4.14 4.15 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. ↑ 5.0 5.1 5.2 5.3 Gauvain G, Chamma I, Chevy Q, Cabezas C, Irinopoulou T, Bodrug N, Carnaud M, Lévi S, Poncer JC (September 2011). "The neuronal K-Cl cotransporter KCC2 influences postsynaptic AMPA receptor content and lateral diffusion in dendritic spines". Proc. Natl. Acad. Sci. U.S.A. 108 (37): 15474–9. doi:10.1073/pnas.1107893108. PMC 3174661. PMID 21878564.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 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.
  7. ↑ 7.0 7.1 7.2 7.3 7.4 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.
  8. ↑ 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.
  9. ↑ 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.
  10. ↑ 10.0 10.1 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.
  11. ↑ 11.0 11.1 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.
  12. ↑ 12.0 12.1 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.
  13. ↑ 13.0 13.1 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.
  14. ↑ Yu, C; Yu, J; Yao, X; Wu, W. K.; 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; et al. (2014). "Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing". Cell Research. 24 (6): 701–12. doi:10.1038/cr.2014.43. PMID 24699064.
  15. ↑ 15.0 15.1 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.
  16. ↑ 16.0 16.1 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.
  17. ↑ 17.0 17.1 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.
  18. ↑ 18.0 18.1 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.
  19. ↑ 19.0 19.1 Chamma I, Heubl M, Chevy Q, Renner M, Moutkine I, Eugène E, Poncer JC, Lévi S (September 2013). "Activity-dependent regulation of the K/Cl transporter KCC2 membrane diffusion, clustering, and function in hippocampal neurons". J. Neurosci. 33 (39): 15488–503. doi:10.1523/JNEUROSCI.5889-12.2013. PMID 24068817.

Further reading

External links

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

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