| Tchem | Solute carrier family 12 member 5 |
Mediates electroneutral potassium-chloride cotransport in mature neurons and is required for neuronal Cl(-) homeostasis. As major extruder of intracellular chloride, it establishes the low neuronal Cl(-) levels required for chloride influx after binding of GABA-A and glycine to their receptors, with subsequent hyperpolarization and neuronal inhibition (By similarity). Involved in the regulation of dendritic spine formation and maturation (PubMed:24668262).
K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene 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. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]
K-Cl cotransporters are proteins that lower intracellular chloride concentrations below the electrochemical equilibrium potential. The protein encoded by this gene 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. Alternative splicing results in two transcript variants encoding different isoforms. [provided by RefSeq, Sep 2008]
Comments
| Disease | Target Count |
|---|---|
| Epilepsy, Temporal Lobe | 23 |
| Hyperalgesia | 71 |
| Seizures | 95 |
| Status Epilepticus | 85 |
| Disease | Target Count | P-value |
|---|---|---|
| ependymoma | 2514 | 3.0174215219456E-28 |
| oligodendroglioma | 2849 | 1.65277822946767E-16 |
| pilocytic astrocytoma | 3086 | 1.50219878553434E-14 |
| atypical teratoid/rhabdoid tumor | 1095 | 3.14087304529765E-14 |
| sonic hedgehog group medulloblastoma | 1482 | 1.34076965560568E-12 |
| pediatric high grade glioma | 2712 | 1.43438724705594E-10 |
| ovarian cancer | 8492 | 5.07929389084395E-10 |
| medulloblastoma, large-cell | 6234 | 2.95797136261265E-8 |
| glioblastoma | 5572 | 4.13254590414756E-7 |
| pituitary cancer | 1972 | 7.82765728155913E-7 |
| primitive neuroectodermal tumor | 3031 | 0.00113226345245496 |
| astrocytoma | 1493 | 0.00178962410638684 |
| subependymal giant cell astrocytoma | 2287 | 0.016620918348208 |
| Pick disease | 1893 | 0.0300939876393433 |
| Disease | Target Count | Z-score | Confidence |
|---|---|---|---|
| Autistic Disorder | 320 | 3.026 | 1.5 |
| Disease | Target Count |
|---|---|
| Epilepsy, Idiopathic Generalized, Susceptibility To, 14 | 1 |
| Temporal lobe epilepsy | 3 |
| Disease | Target Count |
|---|---|
| Epilepsy, idiopathic generalized 14 | 1 |
| Epileptic encephalopathy, early infantile, 34 | 1 |
| Disease | log2 FC | p |
|---|---|---|
| astrocytoma | -3.100 | 0.002 |
| ependymoma | -5.900 | 0.000 |
| oligodendroglioma | -3.100 | 0.000 |
| glioblastoma | -5.000 | 0.000 |
| sonic hedgehog group medulloblastoma | -5.600 | 0.000 |
| atypical teratoid/rhabdoid tumor | -4.800 | 0.000 |
| medulloblastoma, large-cell | -4.600 | 0.000 |
| primitive neuroectodermal tumor | -3.400 | 0.001 |
| pediatric high grade glioma | -4.900 | 0.000 |
| pilocytic astrocytoma | -5.900 | 0.000 |
| subependymal giant cell astrocytoma | -4.225 | 0.017 |
| Pick disease | -1.800 | 0.030 |
| ovarian cancer | 1.900 | 0.000 |
| pituitary cancer | 2.200 | 0.000 |
| Species | Source |
|---|---|
| Chimp | OMA EggNOG |
| Macaque | OMA EggNOG Inparanoid |
| Mouse | OMA EggNOG Inparanoid |
| Rat | OMA EggNOG Inparanoid |
| Dog | OMA EggNOG Inparanoid |
| Horse | OMA EggNOG |
| Cow | OMA EggNOG Inparanoid |
| Pig | OMA EggNOG Inparanoid |
| Opossum | EggNOG Inparanoid |
| Anole lizard | OMA EggNOG Inparanoid |
| Xenopus | OMA EggNOG Inparanoid |
| Zebrafish | OMA Inparanoid |
| AID | Type | Active / Inconclusive / Inactive | Description |
|---|---|---|---|
| 1456 | other |
4127 / 0 / 185148 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS: Primary Screen |
| 1713 | other |
546 / 325 / 2824 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS: Secondary Assay with KCC2 cells |
| 1714 | other |
1815 / 313 / 1567 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS: Secondary Assay 3 with KCC2 cells |
| 1715 | other |
867 / 371 / 2457 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS: Secondary Assay 2 with KCC2 cells |
| 1723 | confirmatory |
8 / 17 / 37 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS: Dose-Dependent Assay 2 with KCC2 |
| 1734 | confirmatory |
22 / 0 / 4 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS: Rubidium Flux |
| 1736 | confirmatory |
92 / 204 / 313 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS; Dose-dependent Assay with KCC2 |
| 1737 | confirmatory |
3 / 9 / 50 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS: Dose-dependent Assay 3 with KCC2 |
| 1799 | summary |
1 / 0 / 0 | Identification of Novel Modulators of Cl- dependent Transport Process via HTS: Antagonist Probe Summary |
| PMID | Text |
|---|---|
| 26733678 | the functional deficit of KCC2 may offer an explanation for the delayed onset of Rett symptoms. |
| 26333769 | A KCC2 mutation causes epilepsy of infancy with migrating focal seizures. Decreased KCC2 expression, reduced protein glycosylation and impaired Cl- extrusion contribute to loss of KCC2 activity, impairing synaptic inhibition and promoting excitability. |
| 26126716 | these data provide insight into the mechanism regulating Cl(-) homeostasis in immature neurons, and suggest that WNK1-regulated changes in KCC2 phosphorylation contribute to the developmental excitatory-to-inhibitory GABA sequence. |
| 26056138 | a novel signaling pathway that couples KCC2 to the cytoskeleton and regulates the formation of glutamatergic synapses. |
| 25947013 | SLC12A5 plays a pivotal oncogenic role in colorectal carcinogenesis; its overexpression is an independent prognostic factor of patients with CRC. |
| 24928908 | These data describe a novel KCC2 variant significantly associated with a human disease and suggest genetically encoded impairment of KCC2 functional regulation may be a risk factor for the development of human IGE. |
| 24699064 | Functional characterization of mutant SLC12A5 revealed its potential oncogenic effect in colon cancer. |
| 24668262 | KCC2-R952H from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. |
| 23894354 | Reduced KCC2/NKCC1 ratio in the cerebrospinal fluid of Rett Syndrome patients suggests a disturbed process of GABAergic neuronal maturation and open up a new therapeutic perspective. |
| 23621303 | Disrupted KCC2 activity seems to be involved in neuropathic pain, epilepsy, motor spasticity, stress and schizophrenia. |
| More... |
MSRRFTVTSLPPAGPARSPDPESRRHSVADPRHLPGEDVKGDGNPKESSPFINSTDTEKGKEYDGKNMAL 1 - 70 FEEEMDTSPMVSSLLSGLANYTNLPQGSREHEEAENNEGGKKKPVQAPRMGTFMGVYLPCLQNIFGVILF 71 - 140 LRLTWVVGIAGIMESFCMVFICCSCTMLTAISMSAIATNGVVPAGGSYYMISRSLGPEFGGAVGLCFYLG 141 - 210 TTFAGAMYILGTIEILLAYLFPAMAIFKAEDASGEAAAMLNNMRVYGTCVLTCMATVVFVGVKYVNKFAL 211 - 280 VFLGCVILSILAIYAGVIKSAFDPPNFPICLLGNRTLSRHGFDVCAKLAWEGNETVTTRLWGLFCSSRFL 281 - 350 NATCDEYFTRNNVTEIQGIPGAASGLIKENLWSSYLTKGVIVERSGMTSVGLADGTPIDMDHPYVFSDMT 351 - 420 SYFTLLVGIYFPSVTGIMAGSNRSGDLRDAQKSIPTGTILAIATTSAVYISSVVLFGACIEGVVLRDKFG 421 - 490 EAVNGNLVVGTLAWPSPWVIVIGSFFSTCGAGLQSLTGAPRLLQAISRDGIVPFLQVFGHGKANGEPTWA 491 - 560 LLLTACICEIGILIASLDEVAPILSMFFLMCYMFVNLACAVQTLLRTPNWRPRFRYYHWTLSFLGMSLCL 561 - 630 ALMFICSWYYALVAMLIAGLIYKYIEYRGAEKEWGDGIRGLSLSAARYALLRLEEGPPHTKNWRPQLLVL 631 - 700 VRVDQDQNVVHPQLLSLTSQLKAGKGLTIVGSVLEGTFLENHPQAQRAEESIRRLMEAEKVKGFCQVVIS 701 - 770 SNLRDGVSHLIQSGGLGGLQHNTVLVGWPRNWRQKEDHQTWRNFIELVRETTAGHLALLVTKNVSMFPGN 771 - 840 PERFSEGSIDVWWIVHDGGMLMLLPFLLRHHKVWRKCKMRIFTVAQMDDNSIQMKKDLTTFLYHLRITAE 841 - 910 VEVVEMHESDISAYTYEKTLVMEQRSQILKQMHLTKNEREREIQSITDESRGSIRRKNPANTRLRLNVPE 911 - 980 ETAGDSEEKPEEEVQLIHDQSAPSCPSSSPSPGEEPEGEGETDPEKVHLTWTKDKSVAEKNKGPSPVSSE 981 - 1050 GIKDFFSMKPEWENLNQSNVRRMHTAVRLNEVIVKKSRDAKLVLLNMPGPPRNRNGDENYMEFLEVLTEH 1051 - 1120 LDRVMLVRGGGREVITIYS 1121 - 1139 //
| PMID | Year | Title |
|---|---|---|
| 26733678 | 2016 | KCC2 rescues functional deficits in human neurons derived from patients with Rett syndrome. |
| 26528127 | 2015 | Regulatory domain or CpG site variation in SLC12A5, encoding the chloride transporter KCC2, in human autism and schizophrenia. |
| 26333769 | 2015 | Mutations in SLC12A5 in epilepsy of infancy with migrating focal seizures. |
| 26126716 | 2015 | WNK1-regulated inhibitory phosphorylation of the KCC2 cotransporter maintains the depolarizing action of GABA in immature neurons. |
| 26056138 | 2015 | KCC2 regulates actin dynamics in dendritic spines via interaction with ?-PIX. |
| 25947013 | 2016 | Increased expression of Solute carrier family 12 member 5 via gene amplification contributes to tumour progression and metastasis and associates with poor survival in colorectal cancer. |
| 24928908 | 2014 | Genetically encoded impairment of neuronal KCC2 cotransporter function in human idiopathic generalized epilepsy. |
| 24699064 | 2014 | Discovery of biclonal origin and a novel oncogene SLC12A5 in colon cancer by single-cell sequencing. |
| 24668262 | 2014 | A variant of KCC2 from patients with febrile seizures impairs neuronal Cl- extrusion and dendritic spine formation. |
| 24393035 | 2014 | The WNK-regulated SPAK/OSR1 kinases directly phosphorylate and inhibit the K+-Cl- co-transporters. |
| More... |
