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This Article Full Text Full Text (PDF) Supplemental Material All Versions of this Article: 296/2/F369    most recent 00096.2008v1 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 Marcano, M. Articles by Moore, L. C. Search for Related Content PubMed PubMed Citation Articles by Marcano, M. Articles by Moore, L. C.

Parameter estimation for mathematical models of NKCC2 cotransporter isoforms

¹Department of Computer Science, University of Puerto Rico, Rio Piedras, Puerto Rico; ²Department of Physiology, Soonchunhyang University, Chungnam, Republic of Korea; ³Department of Applied Mathematics and Statistics, State University of New York at Stony Brook; and ⁴Department of Physiology & Biophysics, State University of New York, Stony Brook, New York

Submitted 25 February 2008 ; accepted in final form 19 November 2008

An optimization problem, formulated using a nonlinear least-squares approach, was used to estimate parameters for kinetic models of the three isoforms of the kidney-specific Na-K-2Cl (NKCC2) cotransporter. Specifically, the optimization problem estimates the magnitude of model parameters (i.e., off-binding and translocation rate constants) by minimizing the distance between model unidirectional fluxes and published unidirectional ⁸⁶Rb⁺ uptake curves for the A, B, and F isoforms of the NKCC2 cotransporter obtained in transfected Xenopus oocytes. By using different symmetry assumptions, NKCC2 models with five, six, seven, or eight parameters were evaluated. The optimization method identified parameter sets that yielded computed unidirectional fluxes consistent with the uptake data. However, the parameter values were not unique, in that systematic exploration of the parameter space revealed alternative parameter sets that fit the data with similar accuracy. Finally, we demonstrate that the optimization method can identify parameter sets for the three transporter isoforms that differ only in ion binding affinities, a result that is consistent with a published mutagenesis analysis of the molecular and structural bases for the differences in ⁸⁶Rb⁺ uptake among the A, B, and F isoforms. These NKCC2 cotransporter models will facilitate the development of larger scale models of ion transport by thick ascending limb cells.

epithelial transport; thick ascending limb; kidney