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The A563T variation of TRPV5 among African Americans significantly enhances TRPV5‐mediated calcium influx
Author(s) -
Na Tao,
Zhang Wei,
Jiang Yi,
Peng JiBin
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.1201.4
Subject(s) - chemistry , endocrinology , calcium , hypercalciuria , medicine , biochemistry , biology , excretion , organic chemistry
The TRPV5 gene, which encodes the renal epithelial Ca 2+ channel, exhibits unusual high frequencies of non‐synonymous single nucleotide polymorphisms (SNP) among African Americans. To evaluate the functional impact of the non‐synonymous SNP variations in TRPV5, A8V, C157R, A563T and L712F variations were introduced to TRPV5 individually, and their abilities to mediated Ca 2+ influx and Na + current were tested using X. laevis oocytes. Among these variants, A563T, which localizes in the last transmembrane domain of TRPV5, exhibited a significant increase in Ca 2+ influx with a concomitant decrease in Na + current as determined by radiotracer uptake and two‐microelectrode voltage clamp, respectively. When threonine 563 was replaced by a serine, Na + current of TRPV5 563S was not much altered while the Ca 2+ influx was reduced as compared to TRPV5 563T . In contrast, when threonine 563 was replaced by a valine, Ca 2+ influx of TRPV5 563V was not much altered while the Na + current was increased as compared to TRPV5 563T . It appears that the hydroxyl group of Thr 563 may hinder the transport of Na + through the channel while the bulky side chain of Thr 563 may facilitate that of Ca 2+ . In conclusion, the A563T variant of TRPV5 significantly increases Ca 2+ influx by altering its cation selectivity. The A563T variation in TRPV5 may contribute to the lower prevalence of hypercalciuria, kidney stone, and osteoporosis among African Americans. Supported by NIH grant DK072154