(serum potassium (K+)concentration is below the normal range), metabolic alkalosis, salt sensiTIvI aldosterone and rennin. Mutations in subunits membrane channels and sustained channel Liddle's syndrome activity. In patients with Liddle's syndrome mutations in the py motifs result in channels The epithelial sodium channel (ENac) is of that cannot be ubiquitinated and are therefore fundamental importance in the control of sodium stabilized resulting in higher-than-normal fluxes in epithelial cells. Modulation of sodium levels of activity reabsorption through the distal nephron ENac is an mportant component in the overall control of sodium balance, blood volume and thereby of blood pressure Image removed due to copyright consideration See Figures 7 in Gormley, K, Dong, Y and Sagnella, GA. 2003. Regulation of the epithelial Image removed due to copyright considerations odium channel by accessory proteins. Biochem. ee Figures 1 in Gormley, K, J.371;1-14 Sagnella, GA. 2003. Regulation of the epithelial sodium channel by accessory proteins. Biochem J.371:1-14 CFTR is needed to regulate ENac activity so both of their functions are knocked-down ENac is composed of a-,B-, and y-subunits in CF that contains Py motifs recognized by ww domains in NEDD4. a member of the Hect E3 ENaC function depends critically on the state ubiquitin ligase family. Its steady state is of CFTR in a purely salt-absorbing epithelium therefore regulated by the ubiquitin Major pathophysiological symptoms of CF proteasome system(endocytosis and lisosomal probably result from an inability of the mutant degradation also play a role in controlling ENac CFTR to inhibit ENaC, manifesting itself in an levels). increased rate of sodium reabsorption in the airway, pancreatic and colonic epithelia of The adrenal hormone aldost erond a maJor affected individuals. The impaired secretion of mechanism in the preservation of salt and CI from the serous cells of airway submucosal water in response to sodium depletion glands and the enhanced absorption of Na and hormone modulates ENaC expression of bsorption of electrolyte and glucocorticoid-regulated kinase-1(SGK1), and water are crucial for the pathophysiology which phosphorylates NEDD4 on serine of the lung disease seen in CF. CF airways are residues, thereby abolishing its interaction unable to enhance their secretory transport with ENaC. Thus, defective regulation of ENac even yperabsorbing due to expression by aldosterone and SGK1 may also enhanced activity of ENaC. This leads to a disturb Na homeostasis and contribute to volume depletion of the airway surface liquid hypertensive states. Lidale's syndrome is an autosomal-dominant form of hypertension characterized by early onset of severe hypertension, hypokalemiaLiddle’s syndrome The epithelial sodium channel (ENaC) is of fundamental importance in the control of sodium fluxes in epithelial cells. Modulation of sodium reabsorption through the distal nephron ENaC is an important component in the overall control of sodium balance, blood volume and thereby of blood pressure. Image removed due to copyright considerations. See Figures 1 in Gormley, K., Dong, Y. and Sagnella, GA. 2003. Regulation of the epithelial sodium channel by accessory proteins. Biochem. J. 371; 1-14. ENaC is composed of α-, β-, and γ-subunits that contains PY motifs recognized by WW domains in NEDD4, a member of the HECT E3 ubiquitin ligase family. Its steady state is therefore regulated by the ubiquitin￾proteasome system (endocytosis and lisosomal degradation also play a role in controlling ENaC levels). The adrenal hormone aldosterone is a major mechanism in the preservation of salt and water in response to sodium depletion. This hormone modulates ENaC expression of serum￾and glucocorticoid-regulated kinase-1 (SGK1), which phosphorylates NEDD4 on serine residues, thereby abolishing its interaction with ENaC. Thus, defective regulation of ENaC expression by aldosterone and SGK1 may also disturb Na+ homeostasis and contribute to hypertensive states. Liddle’s syndrome is an autosomal-dominant form of hypertension characterized by early onset of severe hypertension, hypokalemia (serum potassium (K+) concentration is below the normal range), metabolic alkalosis, salt sensitivity, and low values of serum aldosterone and rennin. Mutations in subunits of ENaC lead to increased numbers of membrane channels and sustained channel activity. In patients with Liddle’s syndrome, mutations in the PY motifs result in channels that cannot be ubiquitinated and are therefore stabilized resulting in higher-than-normal levels of activity. CFTR is needed to regulate ENaC activity so both of their functions are “knocked-down” in CF: ENaC function depends critically on the state of CFTR in a purely salt-absorbing epithelium. Major pathophysiological symptoms of CF probably result from an inability of the mutant CFTR to inhibit ENaC, manifesting itself in an increased rate of sodium reabsorption in the airway, pancreatic and colonic epithelia of affected individuals. The impaired secretion of Cl- from the serous cells of airway submucosal glands and the enhanced absorption of Na+ and consequent hyperabsorption of electrolytes and water are crucial for the pathophysiology of the lung disease seen in CF. CF airways are unable to enhance their secretory transport and may even be hyperabsorbing due to enhanced activity of ENaC. This leads to a volume depletion of the airway surface liquid Image removed due to copyright considerations. See Figures 7 in Gormley, K., Dong, Y. and Sagnella, GA. 2003. Regulation of the epithelial sodium channel by accessory proteins. Biochem. J. 371; 1-14