Disease relevance of Slc26a6

• Calcium oxalate urolithiasis in mice lacking anion transporter Slc26a6 [1].
• Slc26a6-null mice have significant hyperoxaluria and elevation in plasma oxalate concentration that is greatly attenuated by dietary oxalate restriction [1].
• A new study shows that Slc26a6-null mice manifest calcium-oxalate nephrolithiasis accompanied by enhanced net intestinal oxalate absorption [2].
• Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO(3)(-) secretion: relevance to cystic fibrosis [3].
• The mRNA expression of Slc26a3 (downregulated in adenoma) and Slc26a6 (putative anion exchanger-1) was similar between WT and CF duodena [4].

High impact information on Slc26a6

• These findings point to a critical role for Slc26a6 in gastrointestinal oxalate secretion and suggest a genetic explanation for a common form of renal stone disease in humans [2].
• To investigate the possible interaction of NHE3 and CFEX with the PDZ-domain-containing scaffolding protein PDZK1, we performed a series of in vitro interaction assays with GST-fusion proteins and native brush border membrane proteins [5].
• To determine whether PDZK1 interaction is essential for brush border localization of NHE3 and CFEX in vivo, we examined the expression of NHE3 and CFEX in kidneys of wild-type and PDZK1-null mutant mice by both Western analysis and immunocytochemistry [5].
• Functional expression studies in Xenopus oocytes demonstrated that CFEX mediates Cl(-)-formate exchange [6].
• Given its wide tissue distribution, CFEX also may contribute to transcellular Cl(-) transport in additional epithelia such as the pancreas and contribute to transmembrane Cl(-) transport in nonepithelial tissues such as the heart [6].

Chemical compound and disease context of Slc26a6

• Here we show that mutant mice lacking Slc26a6 develop a high incidence of calcium oxalate urolithiasis [1].

Biological context of Slc26a6

• The high 36Cl- transport phenotype cosegregated with the transmembrane domain of mouse Slc26a6 in chimera studies [7].
• Homozygous mutant Slc26a6-/- mice appeared healthy and exhibited a normal blood pressure, kidney function, and plasma electrolyte profile [8].
• Fluid secretory rate in interlobular ducts were comparable in WT and Slc26a6 null mice (P > 0.05) [9].
• In conclusion, these results point to the role of Slc26a6 in HCO(3)(-) efflux at the apical membrane and also suggest the presence of a robust Slc26a3 compensatory upregulation, which can replace the function of Slc26a6 in pancreatic ducts [9].

Anatomical context of Slc26a6

• Whereas Slc26a6 is capable of Cl(-), SO, formate, and oxalate uptake when expressed in Xenopus laevis oocytes, Slc26a1 transports only SO and oxalate [10].
• To assess the contribution of the putative anion transporter (PAT)1 (Slc26a6) to transepithelial oxalate transport, we compared the unidirectional and net fluxes of oxalate across isolated, short-circuited segments of the distal ileum of wild-type (WT) mice and Slc26a6 null mice [knockout (KO)] [11].
• We conclude that Slc26a6 is the predominant Cl(-)-HCO(3)(-) and Cl(-)-OH(-) exchanger of the myocardium and that Slc26a6 is negatively regulated upon alpha-adrenergic stimulation [12].
• We conclude that Slc26a6 mediates oxalate-stimulated NaCl absorption, contributes to apical membrane Cl-/base exchange in the kidney proximal tubule, and also plays an important role in HCO3- secretion in the duodenum [8].
• In the duodenum, the baseline rate of HCO3- secretion measured in mucosal tissue mounted in Ussing chambers was decreased by approximately 30% (P<0.03), whereas the forskolin-stimulated component of HCO3- secretion was the same in wild-type and Slc26a6-/- mice [8].

Associations of Slc26a6 with chemical compounds

• The data indicate that Slc26a6 encodes an apical Cl(-)/formate/oxalate and Cl(-)/base exchanger and reveal significant mechanistic differences between apical and basolateral oxalate exchangers of the proximal tubule [10].
• Measurement of intracellular pH during the removal of extracellular Cl(-) in the presence and absence of HCO indicates that Slc26a6 functions as both a Cl(-)/HCO and a Cl(-)/OH(-) exchanger; simultaneous membrane hyperpolarization during these experimental maneuvers reveals that HCO and OH(-) transport mediated by Slc26a6 is electrogenic [10].
• We conclude that mouse Slc26a6 has affinity for oxalate, sulfate, and HCO(3)(-) in addition to Cl(-) and formate and can function in multiple exchange modes involving pairs of these anions [13].
• Measurements of uptake of [(14)C]oxalate, [(14)C]PAH, and [(35)S]sulfate indicated that Slc26a6 can mediate transport of oxalate and sulfate but not PAH [13].
• Slc26a6: a cardiac chloride-hydroxyl exchanger and predominant chloride-bicarbonate exchanger of the mouse heart [12].

Other interactions of Slc26a6

• Molecular characterization of the murine Slc26a6 anion exchanger: functional comparison with Slc26a1 [10].
• Adult hearts expressed Slc26a3 and Slc4a1-3 mRNAs at similar levels, while Slc26a6 mRNA was about seven-fold higher than AE3, which was more abundant than any other [12].
• We now report the cDNA cloning of CFEX, a mouse pendrin homolog with expression in the kidney by Northern analysis [6].

Analytical, diagnostic and therapeutic context of Slc26a6

• To study its role in kidney and intestinal physiology, gene targeting was used to prepare mice lacking Slc26a6 [8].
• Sequence analysis indicated that CFEX very likely represents the mouse ortholog of human SLC26A6 [6].

References