Protein-protein interactions among ion channels regulate ion transport in the kidney.
Epithelial ion transport in various organs has long been known to be controlled by extracellular agonists acting via membrane receptors or by intracellular messengers. Evidence is mounting for regulation of transport by direct interaction among membrane proteins or between a membrane transport protein and membrane-attached proteins. The membrane protein CFTR (Cystic Fibrosis Transmembrane Regulator) is widely expressed along the length of the nephron, but its role as a chloride channel does not appear to be critical for renal handling of salt and water. It is well established that the inward rectifying K channels (ROMK = Kir 1.1) in the thick ascending limb of Henle and in principal cells of the collecting duct are inhibited by millimolar concentrations of cytosolic Mg-ATP. However, the mechanism of this inhibition has been an enigma. We propose that the ATP-Binding Cassette (ABC) protein CFTR is a cofactor for Kir 1.1 regulation. Indeed, Mg-ATP sensitivity of Kir 1.1 is completely absent in two different mouse models of cystic fibrosis. In addition, the open-closed state of CFTR appears to provide a molecular gating switch that prevents or facilitates the ATP sensing of Kir 1.1. Does Mg-ATP sensing by the CFTR- Kir 1.1 complex play a role in coupling metabolism to ion transport? Physiological intracellular ATP concentrations in tubule cells are in the millimolar range, a saturating concentration for the gating of Kir 1.1 by Mg-ATP. Therefore, Kir 1.1 channels would be closed and unable to contribute to regulation of potassium secretion unless some other process modulated the CFTR-dependent ATP-sensitivity of Kir 1.1. The third component of the metabolic sensor-effector complex for Kir 1.1 regulation is most likely the AMP-regulated serine-threonine kinase, AMP kinase (AMPK). Changing levels in AMP rather than in ATP constitute the metabolic signal "sensed" by tubule cells. Because AMPK inhibits CFTR by modulating CFTR channel gating, we propose that renal K secretion is physiologically regulated by tri-molecular interactions between Kir 1.1, CFTR and AMPK.
Boulpaep
E
E
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, CT 06520, USA.
D000818:Animals; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000502:physiology*; D006801:Humans; D007473:Ion Channels / Q000502:physiology*; D017136:Ion Transport; D007668:Kidney / Q000378:metabolism*; D051379:Mice; D024661:Potassium Channels, Inwardly Rectifying / Q000502:physiology*
D007473:Ion Channels; C086989:KCNJ1 protein, human; D024661:Potassium Channels, Inwardly Rectifying; D019005:Cystic Fibrosis Transmembrane Conductance Regulator