Nils-Alwall-Preisträger 2003 Siegfried Waldegger , Landeck - Österreich Abstract Background: Tubular transepithelial reabsorption of chloride along the nephron is a major determinant of body salt and water homeostasis and blood pressure regulation. About forty percent of the glomerulary filtered sodium chloride are reabsorbed in the distal nephrons. There vectorial transepithelial sodium chloride transport is critically dependent on the function of basolateral ClC-K type chloride channels. Modulation of ClC-Kb chloride channel activity by polymorphic variations of the CLCNKB gene thus could form a molecular basis for salt sensitivity of blood pressure regulation. In this study we tested the effect of several polymorphic variants on ClC-Kb chloride channel activity. Methods: After heterologous expression in Xenopus oocytes, ClC-Kb channel activity and surface expression in presence of the ClC-K beta subunit barttin were determined by two-electrode voltage-clamp analysis, immunofluorescence and ClC-Kb surface ELISA. Results: Chloride currents induced by the ClC-Kb variants L27R, G214A, I419V, T562M, and E578K were not significantly different from wild type currents. The ClC-KbT481S variation however, which showed a frequency of twenty percent in our control population, dramatically activated chloride conductance by a factor of twenty. Activation of chloride currents was also observed after introducing homologous mutations in ClC-Ka and ClC-K1 but not in ClC-2 and ClC-5 chloride channels. ClC-Kb activation by the T481S mutation did not change intrinsic ion channel pore properties and did not require increased surface expression of ClC-KbT481S. Conclusions: Genetic heterogeneity of ClC-Kb chloride channels correlates with functional heterogeneity, which assigns ClC-Kb to a set of genes potentially relevant for polygenic salt-sensitivity of blood pressure regulation. Curriculum Vitae