H,K ATPase Function in Potassium Homeostasis

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DESCRIPTION (provided by applicant): The long-range goal of this research is to determine how ion channels coordinate the regulation of H, K-ATPase activity. We established that barium-sensitive pathways (i.e., ion channels) are required for this H, K-ATPase activity in the renal collecting duct (CD). We also found that fundamental differences exist between the mechanism of activation of H, K-ATPase under K-replete conditions when compared to K- restricted conditions. These observations suggest that ion channels play a fundamental role in the operation of H, K-ATPase activity. Disruption of the KCNQ1 gene or pharmacological blockade of this K channel inhibits gastric acid secretion, which occurs via gastric H, K-ATPase. Our preliminary data demonstrate KCNQ1 expression in the mouse renal CD and its regulation by dietary K content and mineralocorticoids. Thus, we hypothesize that these K channels are essential for the operation of H, K-ATPase activity in the CD and are regulated by dietary K and mineralocorticoids. Accordingly, we propose the following Specific Aims: 1. To define the cellular distribution of KCNQ1 and the response of this K channel to changes in mineralocorticoids and dietary K content normal, HKalpha1 null and HKalpha2 null, and HKbeta null mice. 2. To determine the effect of mineralocorticoids and dietary K intake on steady-state mRNA and protein expression of KCNQ1 and KCNE1-5 in the kidney of normal, HKalpha1 null and HKalpha2 null, and HKbeta null mice. 3. To determine whether disruption of the KCNQ1 gene or highly selective inhibitors of KCNQ1 channel activity alter proton secretion in the CD and the mechanism for H, K-ATPase regulation by KCNQ1. 4. To define the pH dependence of KCNQ1 channels that are expressed in the CD and the gastric parietal cell. With the completion of these studies we will know the molecular identities of the KCNQ1 and KCNE1-5 isoforms that are expressed in the CD, if K intake regulates these isoforms, and the role these molecules play in luminal acidification in the CD. Even modest potassium depletion has been shown to cause renal injury and hypertension. These studies will significantly clarify our understanding of renal K homeostasis and potentially how K depletion exacerbates both renal and cardiovascular disease.