Disease relevance of Slc12a4

• The KCC1 K-Cl cotransporter is a major regulator of erythroid and non-erythroid cell volume, and the KCC1 gene is a candidate modifier gene for sickle cell disease and other hemoglobinopathies [1].
• These results show that KCC1 provides a Cl- extrusion mechanism accompanying the H+ extrusion during bone resorption [2].

High impact information on Slc12a4

• By expression studies in Xenopus oocytes, we show that kinase-active WNK3 increases Cl(-) influx via NKCC1, and that it inhibits Cl(-) exit through KCC1 and KCC2; kinase-inactive WNK3 has the opposite effects [3].
• We show that WNK3, a member of the WNK family of serine-threonine kinases, colocalizes with NKCC1 and KCC1/2 in diverse Cl(-)-transporting epithelia and in neurons expressing ionotropic GABA(A) receptors in the hippocampus, cerebellum, cerebral cortex, and reticular activating system [3].
• Although the two isoforms have equivalent affinities for Cl(-), they differ in the anion selectivity of K(+) transport (Cl(-) > SCN(-) = Br(-) > PO(4)(-3) > I(-) for KCC1 and Cl(-) > Br(-) > PO(4)(-3) = I(-) > SCN(-) for KCC4) [4].
• The existence of KCC1 in the cell membrane of mouse osteoclasts was confirmed by immunochemical staining and Western blot analysis [2].
• KCC1 and chloride channel-7 were found to be expressed in mouse osteoclasts [2].

Biological context of Slc12a4

• Structure and genetic polymorphism of the mouse KCC1 gene [1].
• We have cloned the mouse erythroid KCC1 (mKCC1) cDNA and its flanking genomic regions and mapped the mKCC1 gene to chromosome 8 [5].
• The tissue distributions of mKCC1 mRNA and protein are widespread, and mKCC1 RNA is constitutively expressed during erythroid differentiation of ES cells [5].
• A low-Mg(2+) diet led to diminished urinary K+ excretion, lowered plasma K+ concentration and up-regulation of KCC1 transcripts in the TAL [6].
• A human expressed sequence tag (EST) with high homology to KCC1 was identified [7].

Anatomical context of Slc12a4

• We have investigated the importance of the N- and C-terminal cytoplasmic domains of mouse KCC1 to its K-Cl cotransport function expressed in Xenopus oocytes [8].
• KCC1 polypeptide or related antigen is present in erythrocytes of multiple species in which K-Cl cotransport activity has been documented [5].
• At the time of neurogenesis (embryonic days; E12.5-14.5), KCC1 was only detectable in the developing choroid plexus [9].
• Sickle hemoglobin containing reticulocytes demonstrated KCC isoform expression patterns similar to wild-type cells, except for a consistent difference in the relative abundance of one KCC1 splice variant [10].
• These results establish the presence in rat exocrine glands of KCC1 and likely other KCC polypeptides, and suggest a contribution of KCC polypeptides to transepithelial Cl(-) transport [11].

Associations of Slc12a4 with chemical compounds

• Up-regulation of KCC1 mRNA by dietary Mg(2+) restriction is associated with an increased K+ reabsorption in the in vitro perfused CTAL [6].
• Although mouse KCC1 protein abundance was comparable in MGL and MGH erythrocytes, activities of Src family tyrosine kinases were higher in MGH than in MGL erythrocytes [12].
• Here we examined the expression of six secondary active chloride transporter genes ( NCC, NKCC2, KCC1, KCC3, KCC4, and AE3) in the rat SOC to unravel the molecular mechanisms underlying this change [13].
• Hydropathy analysis reveals the familiar KCC1 topology with 12 transmembrane domains (TMDs) and the hydrophilic NH2-terminal (NTD) and COOH-terminal (CTD) domains both at the cytoplasmic membrane face [14].

Other interactions of Slc12a4

• A highly polymorphic (AC) repeat of mKCC1 intron 1 was characterized in musculus strains, and used to prove lack of linkage between the mKCC1 gene and the rol (resistant to osmotic lysis) locus [1].

Analytical, diagnostic and therapeutic context of Slc12a4

• Three anti-peptide antibodies raised against recombinant mKCC1 function as immunoblot and immunoprecipitation reagents [5].
• Sheep K-Cl cotransporter-1(shKCC1) cDNA was cloned from kidney by RT-PCR with an open reading frame of 3258 base pairs exhibiting 92%, 90%, 88% and 87% identity with pig, rabbit and human, rat and mouse KCC1 cDNAs, respectively, encoding an approximately 122 kDa polypeptide of 1086-amino acids [14].

References