Disease relevance of SLC12A7

• KCC4 is important for recycling Cl(-) for the basolateral anion exchanger in intercalated cells, as is evident from the renal tubular acidosis resulting from its knockout [1].
• IGF-1 upregulates electroneutral K-Cl cotransporter KCC3 and KCC4 which are differentially required for breast cancer cell proliferation and invasiveness [2].

High impact information on SLC12A7

• Substitution of this region in KCC2 with the equivalent sequence of KCC4 resulted in a chimeric KCC that was devoid of isotonic activity, with intact swelling-activated transport [3].
• We report a functional comparison in Xenopus oocytes of KCC1 and KCC4, widely expressed representatives of these two subgroups [4].
• KCC1 and KCC4 exhibit differential sensitivity to transport inhibitors, such that KCC4 is much less sensitive to bumetanide and furosemide [4].
• KCC4 is also uniquely sensitive to 10 mm barium and to 2 mm trichlormethiazide [4].
• We have cloned cDNAs encoding mouse KCC3, human KCC3, and human KCC4, three new members of this gene family [5].

Biological context of SLC12A7

• The human KCC3 and KCC4 genes are located on chromosomes 5p15 and 15q14, respectively [5].
• Initial and steady state kinetics of hKCC2-injected oocytes were performed in both isotonic and hypotonic conditions, revealing K(m)s for K(+) and Cl(-) of 9.3+/-1.8 mM and 6.8+/-0.9 mM, respectively; both affinities are significantly higher than KCC1 and KCC4 [6].
• Finally, both KCC3 and KCC4 are crucial for proximal tubular cell volume regulation [1].
• Consistently, MCF-7 cells obtained advantage in cell proliferation and invasiveness by overexpression of KCC3 and KCC4, respectively [2].
• A canonical tyrosine phosphorylation site is located in the carboxy termini of KCC2 (R1081-Y1087) and KCC4, but not in other KCC isoforms [7].

Anatomical context of SLC12A7

• In addition, we used the polymerase chain reaction to demonstrate the presence of KCC1-KCC4 mRNA in the osteoblast-like cell line [8].
• Thus, KCC4 is expressed on the apical membrane of the choroid plexus, where it likely participates to K(+) reabsorption [9].
• All other brain structures, e.g. cortex, hippocampus, cerebellum showed no KCC4 immunoreactivity, suggesting very low or absent expression of the cotransporter in these regions [9].
• In the embryonic brain, KCC4 mRNA is found in the periventricular zone, cranial nerves and choroid plexus [Eur J Neurosci 16 (2002) 2358] [9].
• Within the brain, the cerebral cortex, hippocampus, and cerebellum revealed minimal KCC4 expression, whereas midbrain and brainstem demonstrated higher levels [9].

Associations of SLC12A7 with chemical compounds

• Localization of the KCC4 potassium-chloride cotransporter in the nervous system [9].
• We postulate that KCC4 mediates potassium and chloride exit from the cell and may play an important role in salt absorption by the distal convoluted tubule [10].

Other interactions of SLC12A7

• Although widely expressed, KCC3 transcripts are the most abundant in heart and kidney, and KCC4 is expressed in muscle, brain, lung, heart, and kidney [5].

Analytical, diagnostic and therapeutic context of SLC12A7

• Of these three isoforms, only SLC12A7 (KCC4) was detected in murine sperm protein by Western blotting [11].
• Of the four KCC genes known to encode the respective proteins and their spliced variants, RT-PCR with both rat and human primers revealed the predicted cDNA fragments of KCC1, KCC3a, KCC3b, and KCC4 but not KCC2 in both HLE-B3 cells and in human lens tissue extracts from cataractous patients [12].

References