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Am J Physiol Cell Physiol 258: C583-C588, 1990;
0363-6143/90 $5.00
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AJP - Cell Physiology, Vol 258, Issue 4 C583-C588, Copyright © 1990 by American Physiological Society

ARTICLES

Irreversible inhibition of renal Na(+)-Pi cotransporter by alpha-bromophosphonoacetic acid

M. Szczepanska-Konkel, A. Hoppe, J. T. Lin and T. P. Dousa
Department of Physiology and Biophysics, Mayo Clinic and Foundation, Mayo Medical School, Rochester, Minnesota 55905.

We investigated the suitability of alpha-bromophosphonoacetic acid (alpha-BrPAA) to act as a possible irreversible inhibitor of Na(+)-dependent transport of Pi across renal brush-border membrane (BBM). When added directly into the Pi uptake medium, alpha-BrPAA causes specific, competitive [apparent inhibition constant (Ki) = 0.33 mM; no change in maximum velocity (Vmax)], and reversible (by washing) inhibition of Na+ gradient [Na+o greater than Na+i]-dependent uptake of Pi by BBM vesicles (BBMV). Next, BBMV were preincubated with 5 mM alpha-BrPAA in alkaline (pH 9) medium for 30 min, then twice washed by 1:100 dilution and recentrifugation, and tested for transport and other properties. This preincubation of BBMV with alpha-BrPAA in alkaline medium resulted in a different type of inhibition [lower Vmax; no change in Michaelis constant (Km)] of the Na+ gradient-dependent uptake of 32Pi, whereas the uptakes of D-[3H]glucose and other solutes were not altered. This inhibition of Pi transport was not reversed by dilution and washing of BBMV. The BBMV Na(+)-dependent binding of [14C]phosphonoformic acid, but not of [3H]phlorizin, was decreased; activities of BBM marker enzymes were not changed. Results suggest that alpha-BrPAA binds onto the same locus on luminal surface of BBM on which Pi and Na+ bind and inhibits Na(+)-Pi cotransporter similar to phosphonoformic acid. Furthermore, after a 30-min incubation in alkaline medium, alpha-BrPAA apparently forms a more stable association with BBM in the vicinity of the Na(+)-Pi cotransporter. We thus suggest that alpha-BrPAA acts under these conditions as an apparently irreversible inhibitor of Na(+)-Pi cotransporter in BBM.(ABSTRACT TRUNCATED AT 250 WORDS)




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