The central focus of the renewal will be on understanding the role of particular ion channels, Ca2+-activated K+ channels, ROMK and CFTR in nephron function and in diseases such as Bartter's syndrome and polycystic kidney disease. This grant is focused on how ion channels work together. The concept of how transport proteins work together to coordinate the transport of solutes and water across epithelial cell membranes has been a question fundamental to epithelial physiology. A combination of molecular and physiological experiments will give us the opportunity to address long standing questions regarding transporter homeostasis. The overall project has three parts: Regulation of Ca+2-activated K+ channels in the Distal Nephron by Alternate Splicing. The precise role in renal K+ transport of two new isoforms of Ca+2-activated K+ channels, one with increased Ca2+-sensitivity (rblso1) and another with a unique PDZ binding domain in the C-terminal tail (rblso2) will be evaluated. The hypothesis to be tested is that these isoforms play a role in K+ secretion in the collecting ducts. Function consequence of the interaction between ROMK and CFTR. The interaction of CFTR with ROMK will be explored. The hypothesis is that interaction of ROMK and CFTR is essential for ROMK function and involves accessory proteins. Role of ion channels in fluid secretion in PKD The fundamental question of how do cysts form in polycystic kidney disease will be examined. The hypothesis is that protein-protein interactions play a role in cyst formation.
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