Flow-induced K secretion (FIKS) in the cortical collecting duct (CCD) is mediated by large conductance, Ca2+/stretch-activated BK channels, comprised of pore-forming ? subunits (BK?)) and accessory ? subunits. The channel is detected in distinct cellular compartments in unique cell types in the CCD. BK channels are localized to cilia in Na absorbing principal cells (PCs), and we hypothesize that these channels in PC cilia facilitate localized membrane hyperpolarization, mechanoinduced Ca2+ entry through Ca2+-selective channels, and subsequent autocrine/paracrine signaling cascades that modulate transport processes. In contrast, BK channels are localized at the apical membrane of acid-base transporting intercalated cells (ICs), and we hypothesize that these channels in ICs mediate FIKS. These hypotheses will be tested by selectively inactivating Kcnma1, the gene encoding BK?, in PCs or ICs. We will determine whether mice lacking BK?, in ICs exhibit reduced FIKS, and whether mice lacking BK?, in PCs exhibit blunted flow-induced Ca2+ signaling, as well as reduced secretion of autocrine/paracrine signaling factors in response to an increase tubular flow. BK?, expression in ICs is enhanced in response to an increase in dietary K. Recent studies have shown that specific WNK kinases regulate BK?, expression in heterologous expression systems (WNK1 increases and WNK4 inhibits). We anticipate that studies proposed in this application will confirm our preliminary observation that increases in dietary K selectively enhance WNK1 expression in ICs, yet reduce WNK4 expression in both ICs and PCs. We also expect to show that mice with conditional deletion of Wnk1 in ICs exhibit blunted IC BK?, expression and FIKS when fed a high K diet. We anticipate that the proposed studies will uncover mechanisms involved in the development/maintenance of disorders of urinary K excretion and identify potential targets for novel therapies to treat K imbalances.
The proposed studies are designed to examine the molecular mechanisms underlying regulation of BK potassium channels in the distal nephron of the kidney. The studies will help define how these channels, normally quiescent under conditions of low urinary flow rate, are activated to secrete potassium into the urine when urinary flow rates increase and in response to a high potassium diet. This work has the potential to uncover mechanisms involved in the development and/or maintenance of disorders of potassium excretion and identify potential targets for novel therapies to treat imbalances in potassium balance.
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