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This Article Full Text Full Text (PDF) All Versions of this Article: 296/5/F1042    most recent 90771.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Na, T. Articles by Peng, J.-B. Search for Related Content PubMed PubMed Citation Articles by Na, T. Articles by Peng, J.-B.

The A563T variation of the renal epithelial calcium channel TRPV5 among African Americans enhances calcium influx

Division of Nephrology, Department of Medicine, Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 30 December 2008 ; accepted in final form 26 February 2009

The transient receptor potential cation channel, subfamily V, member 5 (TRPV5) gene, which encodes the Ca²⁺ channel in the apical membrane of distal convoluted tubule and connecting tubule of the kidney, exhibits an unusually high frequency of nonsynonymous single nucleotide polymorphisms (SNPs) among African Americans. To assess the functional impacts of the nonsynonymous SNP variations in TRPV5, these variants were analyzed with radiotracer ⁴⁵Ca²⁺ influx assay and the voltage-clamp technique using Xenopus laevis oocytes. Among the variations tested, including A8V, R154H, A563T, and L712F, the latter two significantly increased TRPV5-mediated Ca²⁺ influx. The A563T variant, which exists in African Americans with relative high frequency, exhibited increased Ca²⁺ influx at extracellular Ca²⁺ from 0.01 to 2 mM despite a lower expression level at the plasma membrane. This variant also exhibited a reduction in Na⁺ current as a result of increased sensitivity to extracellular Mg²⁺. By substituting threonine-563 (Thr⁵⁶³) with serine or valine residue, the bulky side chain of Thr⁵⁶³ was shown to facilitate Ca²⁺ transport, whereas the hydroxyl group of Thr⁵⁶³ is likely related to Mg²⁺ sensitivity. The A563T variant was capable of increasing TRPV5-mediated Ca²⁺ influx, even when it was expressed under conditions mimicking heterozygous or compound state with other variants. In conclusion, the A563T variant of TRPV5 significantly increased Ca²⁺ influx by affecting the Ca²⁺ permeation pathway. Thus the A563T variation in TRPV5 may contribute to the superior ability of renal Ca²⁺ conservation in African Americans.

single nucleotide polymorphisms; transient receptor potential cation channel, subfamily V, member 5; calcium reabsorption; African Americans