title: Exploring the intricate regulatory network controlling the thiazide-sensitive NaCl cotransporter (NCC).
abstract: The thiazide-sensitive NaCl cotransporter (NCC) plays key roles in renal electrolyte transport and blood pressure maintenance. Regulation of this cotransporter has received increased attention recently, prompted by the discovery that mutations in the with-no-lysine (WNK) kinases are the molecular explanation for pseudohypoaldosteronism type II (PHAII). Studies suggest that WNK4 regulates NCC via two distinct pathways, depending on its state of activation. Furthermore, an intact STE20-related proline-alanine-rich kinase (SPAK)/oxidative stress response 1 kinase (OSR1) pathway was found to be necessary for a WNK4 PHAII mutation to increase NCC phosphorylation and blood pressure in mice. The mouse protein 25α is a novel regulator of the SPAK/OSR1 kinase family, which greatly increases their activity. The phosphorylation status of NCC and the WNK is regulated by the serum- and glucocorticoid-inducible kinase 1, suggesting novel mechanisms whereby aldosterone modulates NCC activity. Dephosphorylation of NCC by protein phosphatase 4 strongly influences the activity of the cotransporter, confirming an important role for NCC phosphorylation. Finally, γ-adducin increases NCC activity. This stimulatory effect is dependent on the phosphorylation status of the cotransporter. γ-Adducin only binds the dephosphorylated cotransporter, suggesting that phosphorylation of NCC causes the dissociation of γ-adducin. Since γ-adducin is not a kinase, it is tempting to speculate that the protein exerts its function by acting as a scaffold between the dephosphorylated cotransporter and the regulatory kinase. As more molecular regulators of NCC are identified, the system-controlling NCC activity is becoming increasingly complex. This intricacy confers an ability to integrate a variety of stimuli, thereby regulating NCC transport activity and ultimately blood pressure.
authors.affiliation: Membrane Protein Disease Research Group, Department of Physiology, 2B2.42 Walter C MacKenzie Centre, University of Alberta, Edmonton T6G 2R7, Alberta, Canada. dimke@ualberta.ca
authors.forename: Henrik
authors.initials: H
authors.lastname: Dimke
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002148:Calmodulin-Binding Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000235:genetics / Q000378:metabolism; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011546:Pseudohypoaldosteronism / Q000503:physiopathology; D011955:Receptors, Drug / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012965:Sodium Chloride / Q000378:metabolism*; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D049971:Thiazides / Q000378:metabolism*; D000099291:Adducins; D000099184:Serum-Glucocorticoid Regulated Kinases; D000099317:Hippo Kinases
chemical_list: D002135:Calcium-Binding Proteins; D002148:Calmodulin-Binding Proteins; D017874:Immediate-Early Proteins; D009419:Nerve Tissue Proteins; D010749:Phosphoprotein Phosphatases; D017346:Protein Serine-Threonine Kinases; D011955:Receptors, Drug; D012965:Sodium Chloride; D064486:Solute Carrier Family 12, Member 3; D027981:Symporters; D049971:Thiazides; D000099291:Adducins; D000099184:Serum-Glucocorticoid Regulated Kinases; C540569:CAB39 protein, human; C578874:SLC12A3 protein, human; C109163:STK24 protein, human; D000099317:Hippo Kinases; C433806:WNK4 protein, human; C080406:protein phosphatase 4