Functional Analysis and Molecular Modeling of a Cloned Urate Transporter/Channel |
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Authors: | E Leal-Pinto BE Cohen RG Abramson |
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Institution: | (1) Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, Box #1243, One Gustave L. Levy Place, New York, NY 10029, USA, US;(2) Department of Anatomy and Cell Biology, Uniformed Services University School of Medicine, Building B, Room B2200, 4301 Jones Bridge Rd., Bethesda, MD 20819, USA, US;(3) Division of Nephrology, Department of Medicine, Mount Sinai School of Medicine, Box #1243, One Gustave L. Levy Place, New York, New York 10029, USA, US |
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Abstract: | Recombinant protein, designated UAT, prepared from a cloned rat renal cDNA library functions as a selective voltage-sensitive
urate transporter/channel when fused with lipid bilayers. Since we previously suggested that UAT may represent the mammalian
electrogenic urate transporter, UAT has been functionally characterized in the presence and absence of potential channel blockers,
several of which are known to block mammalian electrogenic urate transport. Two substrates, oxonate (a competitive uricase
inhibitor) and pyrazinoate, that inhibit renal electrogenic urate transport also block UAT activity. Of note, oxonate selectively
blocks from the cytoplasmic side of the channel while pyrazinoate only blocks from the channel's extracellular face. Like
oxonate, anti-uricase (an electrogenic transport inhibitor) also selectively blocks channel activity from the cytoplasmic
side. Adenosine blocks from the extracellular side exclusively while xanthine blocks from both sides. These effects are consistent
with newly identified regions of homology to uricase and the adenosine A1/A3 receptor in UAT and localize these homologous
regions to the cytoplasmic and extracellular faces of UAT, respectively. Additionally, computer analyses identified four putative
α-helical transmembrane domains, two β sheets, and blocks of homology to the E and B loops of aquaporin-1 within UAT. The experimental observations substantiate our proposal that UAT is the molecular representation
of the renal electrogenic urate transporter and, in conjunction with computer algorithms, suggest a possible molecular structure
for this unique channel.
Received: 13 October 1998/Revised: 28 January 1999 |
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Keywords: | : Adenosine receptor — Transport — Channel — Urate — Galectin — Uricase |
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