As a consequence of a broad spectrum of pathologic disorders, derangement in renal potassium excretion and subsequent alterations in extracellular potassium levels may have profound and even life-threatening effects on cell and organ function. Normally, potassium homeostasis is maintained largely through the regulation of unique, renal cortical collecting duct (CCD) K channels; the activity of these transport elements ultimately dictates the extent of urinary K excretion. To provide a rational framework for elucidating the defects in disorders of potassium homeostasis and designing more effective and specific treatments, it is essential to elucidate the molecular mechanisms governing the modulation of these channels. As the initial step in such an effort, l have recently employed an expression cloning strategy to isolate a novel K channel cDNA, we call CDK1, from a cortical collecting duct cell line. Based functional similarities between the CDK1 channel expressed in Xenopus oocytes and the native CCD K channel, the CDK1 cDNA is likely to encode the major- functional unit, the conductive-pore, of the cortical collecting duct secretory K channel. As a logical extension of these studies, a multidisciplinary approach combining electrophysiology, biochemistry and molecular biological techniques will be employed to l) address the hypothesis that CDK1 encodes the secretory K channel mediating urinary K excretion. 2) determine the molecular basis of the major avenues of short- term CCD K channel regulation and 3) determine the molecular basis for CCD K channel diversity. These studies represent a timely and important extension of the principal investigator's work, and should ultimately provide considerable insight into the basis of disorders in renal K handling and K homeostasis.
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