Na+-sulfate cotransporter SLC13A1.

Sulfate is essential for normal physiology. The kidney plays a major role in sulfate homeostasis. Sulfate is freely filtered and strongly reabsorbed in the proximal tubule.

Regulation of murine hepatic hydroxysteroid sulfotransferase expression in hyposulfatemic mice and in a cell model of 3'-phosphoadenosine-5'-phosphosulfate deficiency.

The cytosolic sulfotransferases (SULTs) catalyze the sulfate conjugation of nucleophilic substrates, and the cofactor for sulfonation, 3'-phosphoadenosine-5'-phosphosulfate (PAPS), is biosynthesized from sulfate and ATP. The phenotype of male knockout mice for the NaS1 sodium sulfate cotransporter includes hyposulfatemia and increased hepatic expression of mouse cytoplasmic sulfotransferase Sult2a and Sult3a1. Here we report that in 8-week-old female NaS1-null mice, hepatic Sult2a1 mRNA levels were ∼51-fold higher than they were in a wild-type liver but expression of no other Sult was affected.

Sodium-sulfate/carboxylate cotransporters (SLC13).

The SLC13 gene family is comprised of five sequence related proteins that are found in animals, plants, yeast and bacteria. Proteins encoded by the SLC13 genes are divided into the following two groups of transporters with distinct anion specificities: the Na(+)-sulfate (NaS) cotransporters and the Na(+)-carboxylate (NaC) cotransporters. Members of this gene family (in ascending order) are: SLC13A1 (NaS1), SLC13A2 (NaC1), SLC13A3 (NaC3), SLC13A4 (NaS2) and SLC13A5 (NaC2).

Sat1 is dispensable for active oxalate secretion in mouse duodenum.

Mice deficient for the apical membrane oxalate transporter SLC26A6 develop hyperoxalemia, hyperoxaluria, and calcium oxalate stones due to a defect in intestinal oxalate secretion. However, the nature of the basolateral membrane oxalate transport process that operates in series with SLC26A6 to mediate active oxalate secretion in the intestine remains unknown. Sulfate anion transporter-1 (Sat1 or SLC26A1) is a basolateral membrane anion exchanger that mediates intestinal oxalate transport.

Slc13a1 and Slc26a1 KO models reveal physiological roles of anion transporters.

Anion transporters NaS1 (SLC13A1) and Sat1 (SLC26A1) mediate sulfate (re)absorption across renal proximal tubule and small intestinal epithelia, thereby regulating blood sulfate levels. Disruption of murine NaS1 and Sat1 genes leads to hyposulfatemia and hypersulfaturia. Sat1-null mice also exhibit hyperoxalemia, hyperoxaluria, and calcium oxalate urolithiasis.

Increased lifespan in hyposulfatemic NaS1 null mice.

Sulfate (SO(4)(2-)) plays an important role in mammalian growth and development. In this study, hyposulfatemic NaS1 null (Nas1-/-) mice were used to investigate the consequences of perturbed SO(4)(2-) homeostasis on longevity. Median life spans were increased (by ≈25%) in male and female Nas1-/- mice when compared with Nas1+/+ mice.

Physiological roles of renal anion transporters NaS1 and Sat1.

This review will briefly summarize current knowledge on the renal anion transporters sodium-sulfate cotransporter-1 (NaS1; Slc13a1) and sulfate-anion transporter-1 (Sat1; Slc26a1). NaS1 and Sat1 mediate renal proximal tubular sulfate reabsorption and thereby regulate blood sulfate levels. Sat1 also mediates renal oxalate transport and controls blood oxalate levels.

Fetal loss and hyposulfataemia in pregnant NaS1 transporter null mice.

Sulfate is important for growth and development, and is supplied from mother to fetus throughout pregnancy. We used NaS1 sulfate transporter null (Nas1(-/-)) mice to investigate the role of NaS1 in maintaining sulfate homeostasis during pregnancy and to determine the physiological consequences of maternal hyposulfataemia on fetal, placental and postnatal growth. We show that maternal serum (≤0.

Physiological roles of mammalian sulfate transporters NaS1 and Sat1.

This review summarizes the physiological roles of the renal sulfate transporters NaS1 (Slc13a1) and Sat1 (Slc26a1). NaS1 and Sat1 encode renal anion transporters that mediate proximal tubular sulfate reabsorption and thereby regulate blood sulfate levels. Targeted disruption of murine NaS1 and Sat1 leads to hyposulfatemia and hypersulfaturia.

Urolithiasis and hepatotoxicity are linked to the anion transporter Sat1 in mice.

Urolithiasis, a condition in which stones are present in the urinary system, including the kidneys and bladder, is a poorly understood yet common disorder worldwide that leads to significant health care costs, morbidity, and work loss. Acetaminophen-induced liver damage is a major cause of death in patients with acute liver failure. Kidney and urinary stones and liver toxicity are disturbances linked to alterations in oxalate and sulfate homeostasis, respectively.

Enhanced tumor growth in the NaS1 sulfate transporter null mouse.

Sulfate plays an important role in maintaining normal structure and function of tissues, and its content is decreased in certain cancers including lung carcinoma. In this study, we investigated tumor growth in a mouse model of hyposulfatemia (Nas1(-/-)) and compared it to wild-type (Nas1(+/+)) mice. Lung epithelial tumor cells (TC-1 cell line) were injected subcutaneously into male Nas1(-/-) and Nas1(+/+) mice on a mixed 129Sv and C57BL/6 genetic background.

Expression cloning and radiotracer uptakes in Xenopus laevis oocytes.

This protocol describes the method of expression cloning of heterologous proteins using Xenopus laevis oocytes and the functional characterization of membrane proteins using radiotracer assays. It can be used to isolate proteins for which sequence data is unavailable and to characterize the functions of proteins. A cDNA library is generated, that is, translated into proteins in Xenopus oocytes, and the function of these proteins is assessed by a radiotracer assay.

Kidney transcriptome reveals altered steroid homeostasis in NaS1 sulfate transporter null mice.

Sulfate is essential for human growth and development, and circulating sulfate levels are maintained by the NaS1 sulfate transporter which is expressed in the kidney. Previously, we generated a NaS1-null (Nas1(-/-)) mouse which exhibits hyposulfatemia. In this study, we investigated the kidney transcriptome of Nas1(-/-) mice.

Functional and structural characterization of the zebrafish Na+-sulfate cotransporter 1 (NaS1) cDNA and gene (slc13a1).

Sulfate plays an essential role during growth, development and cellular metabolism. In this study, we characterized the function and structure of the zebrafish (Danio rerio) Na+-sulfate cotransporter 1 (NaS1) cDNA and gene (slc13a1). Zebrafish NaS1 encodes a protein of 583 amino acids with 13 putative transmembrane domains.

Monitoring protein-protein interactions between the mammalian integral membrane transporters and PDZ-interacting partners using a modified split-ubiquitin membrane yeast two-hybrid system.

PDZ-binding motifs are found in the C-terminal tails of numerous integral membrane proteins where they mediate specific protein-protein interactions by binding to PDZ-containing proteins. Conventional yeast two-hybrid screens have been used to probe protein-protein interactions of these soluble C termini. However, to date no in vivo technology has been available to study interactions between the full-length integral membrane proteins and their cognate PDZ-interacting partners.

Hyperserotonaemia and reduced brain serotonin levels in NaS1 sulphate transporter null mice.

Sulphate (SO4) is conjugated to numerous endogenous compounds, including serotonin (5-HT). The NaS1 sulphate transporter is primarily expressed in the kidney, where it maintains blood SO4 concentrations. Previously, we generated NaS1 null (Nas1) mice, which have hyposulphataemia and decreased anxiety and locomotor activity.

Quaternary structure and apical membrane sorting of the mammalian NaSi-1 sulfate transporter in renal cell lines.

NaSi-1 encodes a Na(+)-sulfate cotransporter expressed on the apical membrane of renal proximal tubular cells, which is responsible for body sulfate homeostasis. Limited information is available on NaSi-1 protein structure and the mechanisms controlling its apical membrane sorting. The aims of this study were to biochemically determine the quaternary structure of the rat NaSi-1 protein and to characterize its expression in renal epithelial cell lines.

Sulfate transport by SLC26 transporters.

Sulfate is the fourth most abundant anion in human plasma that is essential for numerous physiological functions, including biotransformation of xenobiotics, steroids, non-steroidal anti-inflammatory drugs (NSAIDs), adrenergic stimulants/blockers and analgesics. Sulfate is also required for activation of many endogenous compounds (heparin, heparan sulfate, dermatan sulfate, bile acids) and utilized in the metabolism of neurotransmitters. Sulfation of structural components, including glycosaminoglycans and cerebroside sulfate, is essential for the maintenance of normal structure and function of tissues.

Molecular cloning and characterization of the mouse Na+ sulfate cotransporter gene (Slc13a4): Structure and expression.

Sulfate is an essential ion required for numerous functions in mammalian physiology. Due to its hydrophilic nature, cells require sulfate transporters on their plasma membranes to allow entry of sulfate into cells. In this study, we identified a new mouse Na(+)-sulfate cotransporter (mNaS2), characterized its tissue distribution and determined its cDNA and gene (Slc13a4) structures.

Specificity and regulation of renal sulfate transporters.

Sulfate is essential for normal cellular function. The kidney plays a major role in sulfate homeostasis. Sulfate is freely filtered and then undergoes net reabsorption in the proximal tubule.

Disruption of NaS1 sulfate transport function in mice leads to enhanced acetaminophen-induced hepatotoxicity.

Sulfate is required for detoxification of xenobiotics such as acetaminophen (APAP), a leading cause of liver failure in humans. The NaS1 sulfate transporter maintains blood sulfate levels sufficiently high for sulfonation reactions to work effectively for drug detoxification. In the present study, we identified two loss-of-function polymorphisms in the human NaS1 gene and showed the Nas1-null mouse to be hypersensitive to APAP hepatotoxicity.

Transcriptional profile reveals altered hepatic lipid and cholesterol metabolism in hyposulfatemic NaS1 null mice.

Sulfate plays an essential role in human growth and development, and its circulating levels are maintained by the renal Na+-SO42- cotransporter, NaS1. We previously generated a NaS1 knockout (Nas1-/-) mouse, an animal model for hyposulfatemia, that exhibits reduced growth and liver abnormalities including hepatomegaly. In this study, we investigated the hepatic gene expression profile of Nas1-/- mice using oligonucleotide microarrays.

The rat Na+-sulfate cotransporter rNaS2: functional characterization, tissue distribution, and gene (slc13a4) structure.

Inorganic sulfate is essential for numerous functions in mammalian physiology. In the present study, we characterized the functional properties of the rat Na+-sulfate cotransporter NaS2 (rNaS2), determined its tissue distribution, and identified its gene (slc13a4) structure. Expression of rNaS2 protein in Xenopus oocytes led to a Na+-dependent transport of sulfate that was inhibited by phosphate, thiosulfate, tungstate, selenate, oxalate, and molybdate, but not by citrate, succinate, or DIDS.

NaSi-1 and Sat-1: structure, function and transcriptional regulation of two genes encoding renal proximal tubular sulfate transporters.

Sulfate (SO(4)2-) is an important anion regulating many metabolic and cellular processes. Maintenance of SO4(2-) homeostasis occurs in the renal proximal tubule via membrane transport proteins. Two SO(4)2- transporters that have been characterized and implicated in regulating serum SO4(2-) levels are: NaSi-1, a Na+-SO(4)2- cotransporter located at the brush border membrane and Sat-1, a SO4(2-)-anion exchanger located on the basolateral membranes of proximal tubular cells.

Control of ion transport in mammalian airways by protease activated receptors type 2 (PAR-2).

Protease-activated receptors (PARs) are widely distributed in human airways. They couple to G- proteins and are activated after proteolytic cleavage of the N terminus of the receptor. Evidence is growing that PAR subtype 2 plays a pivotal role in inflammatory airway diseases, such as allergic asthma or bronchitis.