Membrane Processes Mediating K Secretion

Weill Medical Coll Of Cornell Univ, New York NY

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Abstract

The kidney maintains the balance of potassium (K) in the body by excreting in the urine about the same amount of K that is ingested in the diet. Under most conditions it does this by secreting K into the urine in the distal nephron and collecting duct. The mechanism involves, at least in part, the movement of K from the cells into the urine through ion channels in the apical membrane. The connecting tubule (CNT), a segment joining the distal convoluted tubule and the cortical collecting duct (CCD)is an important site for K secretion. We have indentified two K channels in the apical membrane of the rat CNT:a low conductance (SK, ROMK) channel and a high conductance (BK, maxi-K) channel. Here we propose to examine the regulation of these channels in the CNT.In our initial findings the abudnance of SK channels was not increased in the CNT as it was in the CCD when the animal s. We will test whether the set-point for regulation is shifted in the CNT.Alternatively, we will examine whether the difference is related to the ROMK isoform which is expressed. We will also examine the regulation of the SK channels by peptide hormones including ADH and glucagon. The BK channels were observed primarily in the intercalated cells of the CNT. We will ask whether the low open probability of these channels under resting conditions can be increased sufficiently for them to contribute to K secretion. Stimuli will include hormone stimulation and increased shear stress on the membrane. We will also ask whether K uptake by the intercalated cells through the Na/K-ATPase is adequate to support a significant K secretion. Finally, we will quantify K secretion in the distal nephron under various conditions and ask whether it can be accounted for by the measured electrophysiological properties of the cells. A second set of aims will focus on the process of permeation through SK/ROMK channels. We will test the hypothesis that this K movement involves transport through the "cytoplasmic pore", a part of the channel protein which protrudes into the cytoplasm and is unique to the inward-rectifier K channel family. We will further examine the mechanism of saturation of channel condutance using a site-directed mutagenesis approach. These studies should elucidate the processes of how the kidney maintains plasma K under tight control. Loss of this control, for example in genetic diseases such as Bartter's or Gitelman's syndromes, has serious consequences including altered cell excitability, cardiac arrhythmias and muscle weakness.