Human SLC2A9a and SLC2A9b isoforms mediate electrogenic transport of urate with different characteristics in the presence of hexoses

Abstract

Human SLC2A9 (GLUT9) is a novel high-capacity urate transporter belonging to the facilitated glucose transporter family. In the present study, heterologous expression in Xenopus oocytes has allowed us to undertake an in-depth radiotracer flux and electrophysiological study of urate transport mediated by both isoforms of SLC2A9 (a and b). Addition of urate to SLC2A9-producing oocytes generated outward currents, indicating electrogenic transport. Urate transport by SLC2A9 was voltage dependent and independent of the Na(+) transmembrane gradient. Urate-induced outward currents were affected by the extracellular concentration of Cl(-), but there was no evidence for exchange of the two anions. [(14)C]urate flux studies under non-voltage-clamped conditions demonstrated symmetry of influx and efflux, suggesting that SLC2A9 functions in urate efflux driven primarily by the electrochemical gradient of the cell. Urate uptake in the presence of intracellular hexoses showed marked differences between the two isoforms, suggesting functional differences between the two splice variants. Finally, the permeant selectivity of SLC2A9 was examined by testing the ability to transport a panel of radiolabeled purine and pyrimidine nucleobases. SLC2A9 mediated the uptake of adenine in addition to urate, but did not function as a generalized nucleobase transporter. The differential expression pattern of the two isoforms of SLC2A9 in the human kidney's proximal convoluted tubule and its electrogenic transport of urate suggest that these transporters play key roles in the regulation of plasma urate levels and are therefore potentially important participants in hyperuricemia and hypouricemia.

Critical Roles of Two Hydrophobic Residues within Human Glucose Transporter 9 (hSLC2A9) in Substrate Selectivity and Urate Transport

“…Detailed characterization of hSLC2A9 indicates that this transporter exhibits hexose/hexose transacceleration and hexose/urate exchange across the cell membrane (13,14). That is, hexose on one side of the membrane can stimulate the unidirectional flow of hexose or urate from the other side of the membrane.…”

Case Report SLC2A9 and ZNF518B polymorphisms correlate with gout-related metabolic indices in Chinese Tibetan populations

“…It is a causative gene for renal hypouricemia and plays a key role in urate reabsorption by renal proximal tubular cells (Preitner et al, 2009). Recently, studies have reported that SLC2A9 plays a crucial role in the incidence of gout (Tin et al, 2011;Witkowska et al, 2012). Another study showed that rs13129697, located in intron 7 of SLC2A9, showed the strongest association with gout (Karns et al, 2012).…”

“…Among these, the most significant findings include single nucleotide polymorphisms (SNPs) located within the SLC2A9 gene and the intergenic region between SLC2A9 and ZNF518B on chromosome 4 (Döring et al, 2008). SLC2A9 encodes the GLUT9 renal molecule, which transports glucose and later transports uric acid (Caulfield et al, 2008;Witkowska et al, 2012). ZNF518B is a novel gene that has been identified to be associated with gout (Döring et al, 2008).…”

Uric acid transporter inhibitors for gout

“…Similar to other members of the SLC2 family, GLUT9 has been shown to transport glucose and other sugars, although this has recently been questioned [21]. However, sugars may influence the transport of urate by GLUT9 [22], suggesting that dietary sugars can influence sUA levels through GLUT9. A short isoform of GLUT9 (GLUT9b or -S) differs at the amino terminus from the longer isoform due to alternative splicing.…”