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Articles by B. E Shmukler
Total Records ( 5 ) for B. E Shmukler
  C Xu , B. E Shmukler , K Nishimura , E Kaczmarek , S Rossetti , P. C Harris , A Wandinger Ness , R. L Bacallao and S. L. Alper

Flow-induced cytosolic Ca2+ Cai2+ signaling in renal tubular epithelial cells is mediated in part through P2 receptor (P2R) activation by locally released ATP. The ability of P2R to regulate salt and water reabsorption has suggested a possible contribution of ATP release and paracrine P2R activation to cystogenesis and/or enlargement in autosomal dominant polycystic kidney disease (ADPKD). We and others have demonstrated in human ADPKD cyst cells the absence of flow-induced Cai2+ signaling exhibited by normal renal epithelial cells. We now extend these findings to primary and telomerase-immortalized normal and ADPKD epithelial cells of different genotype and of both proximal and distal origins. Flow-induced elevation of Cai2+ concentration ([Ca2+]i) was absent from ADPKD cyst cells, but in normal cells was mediated by flow-sensitive ATP release and paracrine P2R activation, modulated by ecto-nucleotidase activity, and abrogated by P2R inhibition or extracellular ATP hydrolysis. In contrast to the elevated ATP release from ADPKD cells in static isotonic conditions or in hypotonic conditions, flow-induced ATP release from cyst cells was lower than from normal cells. Extracellular ATP rapidly reduced thapsigargin-elevated [Ca2+]i in both ADPKD cyst and normal cells, but cyst cells lacked the subsequent, slow, oxidized ATP-sensitive [Ca2+]i recovery present in normal cells. Telomerase-immortalized cyst cells also exhibited altered CD39 and P2X7 mRNA levels. Thus the loss of flow-induced, P2R-mediated Cai2+ signaling in human ADPKD cyst epithelial cells was accompanied by reduced flow-sensitive ATP release, altered purinergic regulation of store-operated Ca2+ entry, and altered expression of gene products controlling extracellular nucleotide signaling.

  J. F Heneghan , A Akhavein , M. J Salas , B. E Shmukler , L. P Karniski , D. H Vandorpe and S. L. Alper

Nephrolithiasis in the Slc26a6–/– mouse is accompanied by 50–75% reduction in intestinal oxalate secretion with unchanged intestinal oxalate absorption. The molecular identities of enterocyte pathways for oxalate absorption and for Slc26a6-independent oxalate secretion remain undefined. The reported intestinal expression of SO42– transporter SLC26A2 prompted us to characterize transport of oxalate and other anions by human SLC26A2 and mouse Slc26a2 expressed in Xenopus oocytes. We found that hSLC26A2-mediated [14C]oxalate uptake (K1/2 of 0.65 ± 0.08 mM) was cis-inhibited by external SO42– (K1/2 of 3.1 mM). hSLC26A2-mediated bidirectional oxalate/SO42– exchange exhibited extracellular SO42– K1/2 of 1.58 ± 0.44 mM for exchange with intracellular [14C]oxalate, and extracellular oxalate K1/2 of 0.14 ± 0.11 mM for exchange with intracellular 35SO42–. Influx rates and K1/2 values for mSlc26a2 were similar. hSLC26A2-mediated oxalate/Cl exchange and bidirectional SO42–/Cl exchange were not detectably electrogenic. Both SLC26A2 orthologs exhibited nonsaturable extracellular Cl dependence for efflux of intracellular [14C]oxalate, 35SO42–, or 36Cl. Rate constants for 36Cl efflux into extracellular Cl, SO42–, and oxalate were uniformly 10-fold lower than for oppositely directed exchange. Acidic extracellular pH (pHo) inhibited all modes of hSLC26A2-mediated anion exchange. In contrast, acidic intracellular pH (pHi) selectively activated exchange of extracellular Cl for intracellular 35SO42– but not for intracellular 36Cl or [14C]oxalate. Protein kinase C inhibited hSLC26A2 by reducing its surface abundance. Diastrophic dysplasia mutants R279W and A386V of hSLC26A2 exhibited similar reductions in uptake of both 35SO42– and [14C]oxalate. A386V surface abundance was reduced, but R279W surface abundance was at wild-type levels.

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