SLC12A6 Membrane Protein Introduction

Introduction of SLC12A6

Solute carrier family 12 member 6 is a protein that in humans is encoded by the SLC12A6 gene. It is an important member of the K-Cl cotransporter (KCC) family. K-Cl cotransporters are integral membrane proteins that lower intracellular chloride concentrations under the electrochemical equilibrium potential. The proteins can be activated by cell swelling resulted from hypotonic conditions. It has many different isoforms, KCC3a and KCC3b included. Mutations in this gene are associated with agenesis of the corpus callosum with peripheral neuropathy.

Basic Information of SLC12A6
Protein Name	Solute carrier family 12 member 6
Gene Name	SLC12A6/KCC3
Aliases	Electroneutral potassium-chloride cotransporter 3, K-Cl cotransporter 3)
Organism	Homo sapiens (Human)
UniProt ID	Q9UHW9
Transmembrane Times	12
Length (aa)	1150
Sequence	MHPPETTTKMASVRFMVTPTKIDDIPGLSDTSPDLSSRSSSRVRFSSRESVPETSRSEPMSEMSGATTSLATVALDPPSDRTSHPQDVIEDLSQNSITGEHSQLLDDGHKKARNAYLNNSNYEEGDEYFDKNLALFEEEMDTRPKVSSLLNRMANYTNLTQGAKEHEEAENITEGKKKPTKTPQMGTFMGVYLPCLQNIFGVILFLRLTWVVGTAGVLQAFAIVLICCCCTMLTAISMSAIATNGVVPAGGSYFMISRALGPEFGGAVGLCFYLGTTFAAAMYILGAIEIFLVYIVPRAAIFHSDDALKESAAMLNNMRVYGTAFLVLMVLVVFIGVRYVNKFASLFLACVIVSILAIYAGAIKSSFAPPHFPVCMLGNRTLSSRHIDVCSKTKEINNMTVPSKLWGFFCNSSQFFNATCDEYFVHNNVTSIQGIPGLASGIITENLWSNYLPKGEIIEKPSAKSSDVLGSLNHEYVLVDITTSFTLLVGIFFPSVTGIMAGSNRSGDLKDAQKSIPIGTILAILTTSFVYLSNVVLFGACIEGVVLRDKFGDAVKGNLVVGTLSWPSPWVIVIGSFFSTCGAGLQSLTGAPRLLQAIAKDNIIPFLRVFGHSKANGEPTWALLLTAAIAELGILIASLDLVAPILSMFFLMCYLFVNLACALQTLLRTPNWRPRFRYYHWALSFMGMSICLALMFISSWYYAIVAMVIAGMIYKYIEYQGAEKEWGDGIRGLSLSAARFALLRLEEGPPHTKNWRPQLLVLLKLDEDLHVKHPRLLTFASQLKAGKGLTIVGSVIVGNFLENYGEALAAEQTIKHLMEAEKVKGFCQLVVAAKLREGISHLIQSCGLGGMKHNTVVMGWPNGWRQSEDARAWKTFIGTVRVTTAAHLALLVAKNISFFPSNVEQFSEGNIDVWWIVHDGGMLMLLPFLLKQHKVWRKCSIRIFTVAQLEDNSIQMKKDLATFLYHLRIEAEVEVVEMHDSDISAYTYERTLMMEQRSQMLRHMRLSKTERDREAQLVKDRNSMLRLTSIGSDEDEETETYQEKVHMTWTKDKYMASRGQKAKSMEGFQDLLNMRPDQSNVRRMHTAVKLNEVIVNKSHEAKLVLLNMPGPPRNPEGDENYMEFLEVLTEGLERVLLVRGGGSEVITIYS

Function of SLC12A6 Membrane Protein

SLC12A6 (KCC3) is a potassium (K⁺)/chloride (Cl^-) symporter that controls chloride homeostasis in neurons. It can mediate electroneutral potassium-chloride cotransport and contribute to cell volume homeostasis in single cells. It has been reported that SLC12A6 can be activated by cell swelling. This protein participates in chloride symporter, potassium ion transmembrane transporter activity and protein kinase binding process. SLC12A6 influences many biological processes, including angiogenesis, cellular hypotonic response, cellular hypotonic salinity response, chemical synaptic transmission, ion transport and potassium ion import.

Fig.1 KCC3 downregulates E-cadherin/β-catenin complex formation by inhibiting transcription of E-cadherin gene and accelerating proteosome-dependent degradation of β-catenin protein. (Hsu, 2007)

Application of SLC12A6 Membrane Protein in Literature

Howard H.C., et al. The K-Cl cotransporter KCC3 is mutant in a severe peripheral neuropathy associated with agenesis of the corpus callosum. Nat Genet. 2002, 32(3):384-92. PubMed ID: 12368912

This article identifies mutations in SLC12A6 as the genetic lesion underlying ACCPN and suggests a critical role for SLC12A6 in the development and maintenance of the nervous system.
Boettger T., et al. Loss of K-Cl co-transporter KCC3 causes deafness, neurodegeneration and reduced seizure threshold. EMBO J. 2003, 22(20):5422-34. PubMed ID: 14532115

The authors find that KCC3 is expressed in many, but not all cells of the inner ear K(+) recycling pathway. Their mouse model successfully explains important cellular and systemic functions of KCC3 and shows great value for Anderman syndrome.
Mercado A., et al. NH2-terminal heterogeneity in the KCC3 K⁺-Cl^- cotransporter. Am J Physiol Renal Physiol. 2005, 289(6):F1246-61. PubMed ID: 16048901

This article suggests that there is significant NH(2)-terminal heterogeneity of KCC3 in the kidney. It is likely for basolateral swelling-activated K(+)-Cl(-) cotransport to function in cell volume regulation during the transepithelial transport of both salt and solutes by the proximal tubule.
Byun N. and Delpire E. Axonal and periaxonal swelling precede peripheral neurodegeneration in KCC3 knockout mice. Neurobiol Dis. 2007, 28(1):39-51. PubMed ID: 17659877

This article supports that fluid-related axonopathy, which will ultimately bring about neurodegeneration, can implicate cell volume regulation as a critical component of peripheral nerve maintenance.
Steinlein O.K., et al. Mutation analysis of the potassium chloride cotransporter KCC3 (SLC12A6) in rolandic and idiopathic generalized epilepsy. Epilepsy Res. 2001, 44(2-3):191-5. PubMed ID: 11325574

This article identifies four novel single nucleotide exchanges (SNPs), none of them changes the coding sequence. It also negatively supports a major role for KCC3 in the etiology of rolandic epilepsy or common subtypes of IGE.

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Reference

Hsu Y M, et al. (2007). KCl cotransporter-3 downregulates E-cadherin/β-catenin complex to promote epithelial-mesenchymal transition. Cancer Res. 67(22):11064-73.

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