(verbatim from application) The overall goals of the proposal (IRPG#3) are to explore the molecular mechanisms of hormonal regulation of ROMK channels and to define the role of ROMK channels in forming apical K + channels in the thick ascending limb (TAL). ROMK channels share the key biophysical properties with the native small-conductance ATP-sensitive K+ channel (SKatp) in the TAL and collecting duct. However, mechanisms by which SKstp is regulated in the TAL are not completely understood since the density of the SKatp is low. This difficulty can now be overcome since preliminary results have demonstrated that in the mouse TAL the density of the apical K channels is significantly increased by either adding forskolin or removal of extracellular Ca2+. Thus, the first goal of Specific Aim 1 is to study the biophysical properties of the apical K+ channels in the mouse TAL. The information will be important for further studying the role of ROMK channels in forming the apical K+ channels when the ROMK‑knockout mice are available. The second goal is to explore the hypothesis that interaction between the vasopressin receptor and the Ca2+-sensing receptor (CaR)-mediated action plays a key role in determining the activity of the apical K+ channels in the mouse TAL. The goal of Specific Aim 2 is to examine the role of kinase anchoring proteins in mediating the effect of PKA and PKC in modulating ROMK channel function and phosphorylation. The goal of Specific Aim 3 is to investigate the mechanism by which PGE2 regulates the apical K+ channels in the TAL. The effect of PGE2 has relevance to Bartter's Syndrome where hyperprostaglandinemia is prominent and inhibition of prostaglandin production reverses partially the physiological consequences of impaired TAL function.
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| Scholl, Ute I; Abriola, Laura; Zhang, Chengbiao et al. (2017) Macrolides selectively inhibit mutant KCNJ5 potassium channels that cause aldosterone-producing adenoma. J Clin Invest 127:2739-2750 |
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| Ellison, David H; Felker, G Michael (2017) Diuretic Treatment in Heart Failure. N Engl J Med 377:1964-1975 |
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