Regulation of the epithelial Na+ channel (ENaC) by phosphatidylinositides.

The epithelial Na(+) channel (ENaC) is an end-effector of diverse cellular signaling cascades, including those with phosphatidylinositide second messengers. Recent evidence also suggests that in some instances, phospatidylinositides can directly interact with ENaC to increase channel activity by increasing channel open probability and/or membrane localization. We review here findings relevant to regulation of ENaC by phosphatidylinositol 4,5-bisphosphate (PIP(2)) and phosphatidylinositol 3,4,5-triphosphate (PIP(3)). Similar to its actions on other ion channels, PIP(2) is permissive for ENaC openings having a direct effect on gating. The PIP(2) binding site in ENaC involved in this regulation is most likely localized to the NH(2) terminus of beta-ENaC. PIP(3) also affects ENaC gating but, rather than being permissive, augments open probability. The PIP(3) binding site in ENaC involved in this regulation is localized to the proximal region of the COOH terminus of gamma-ENaC just following the second transmembrane domain. In complementary pathways, PIP(3) also impacts ENaC membrane levels through both direct actions on the channel and via a signaling cascade involving phosphoinositide 3-OH kinase (PI3-K) and the aldosterone-induced gene product serum and glucocorticoid-inducible kinase. The putative PIP(3) binding site in ENaC involved in direct regulation of channel membrane levels has not yet been identified.

[1]  A. Vandewalle,et al.  Phosphatidylinositol 3,4,5-Trisphosphate Mediates Aldosterone Stimulation of Epithelial Sodium Channel (ENaC) and Interacts with γ-ENaC* , 2005, Journal of Biological Chemistry.

[2]  P. Snyder Minireview: regulation of epithelial Na+ channel trafficking. , 2005, Endocrinology.

[3]  O. Pochynyuk,et al.  Identification of a Functional Phosphatidylinositol 3,4,5-Trisphosphate Binding Site in the Epithelial Na+ Channel* , 2005, Journal of Biological Chemistry.

[4]  C. Nichols,et al.  Direct Modulation of Kir Channel Gating by Membrane Phosphatidylinositol 4,5-Bisphosphate*♦ , 2005, Journal of Biological Chemistry.

[5]  Yang Li,et al.  Regulation of Kv7 (KCNQ) K+ Channel Open Probability by Phosphatidylinositol 4,5-Bisphosphate , 2005, The Journal of Neuroscience.

[6]  Doyun Lee,et al.  Low mobility of phosphatidylinositol 4,5-bisphosphate underlies receptor specificity of Gq-mediated ion channel regulation in atrial myocytes. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[7]  B. Hille,et al.  Regulation of ion channels by phosphatidylinositol 4,5-bisphosphate , 2005, Current Opinion in Neurobiology.

[8]  C. Erneux,et al.  Hydrogen peroxide and epidermal growth factor activate phosphatidylinositol 3-kinase and increase sodium transport in A6 cell monolayers. , 2005, American journal of physiology. Renal physiology.

[9]  O. Pochynyuk,et al.  Ras couples phosphoinositide 3-OH kinase to the epithelial Na+ channel. , 2005, Biochimica et biophysica acta.

[10]  C. Downes,et al.  Probing phosphoinositide functions in signaling and membrane trafficking. , 2005, Trends in cell biology.

[11]  P. Caroni,et al.  PI(4,5)P2-dependent microdomain assemblies capture microtubules to promote and control leading edge motility , 2005, The Journal of cell biology.

[12]  T. Balla,et al.  PIP2 hydrolysis underlies agonist‐induced inhibition and regulates voltage gating of two‐pore domain K+ channels , 2005, The Journal of physiology.

[13]  P. Snyder,et al.  Nedd4-2 Phosphorylation Induces Serum and Glucocorticoid-regulated Kinase (SGK) Ubiquitination and Degradation* , 2005, Journal of Biological Chemistry.

[14]  R. Schreiber,et al.  Purinergic inhibition of the epithelial Na+ transport via hydrolysis of PIP2 , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[15]  Jian Yang,et al.  Phosphotidylinositol 4,5-Bisphosphate Signals Underlie Receptor-Specific Gq/11-Mediated Modulation of N-Type Ca2+ Channels , 2004, The Journal of Neuroscience.

[16]  Jason M. Byars,et al.  Real-time three-dimensional imaging of lipid signal transduction: apical membrane insertion of epithelial Na(+) channels. , 2004, American Journal of Physiology - Cell Physiology.

[17]  N. Zheleznova,et al.  Rho Small GTPases Activate the Epithelial Na+ Channel* , 2004, Journal of Biological Chemistry.

[18]  T. McDonald,et al.  Molecular analysis of PIP2 regulation of HERG and IKr. , 2004, American journal of physiology. Heart and circulatory physiology.

[19]  C. Abrams,et al.  Rho and Rho-kinase Mediate Thrombin-induced Phosphatidylinositol 4-Phosphate 5-Kinase Trafficking in Platelets* , 2004, Journal of Biological Chemistry.

[20]  K. Jakobs,et al.  Regulation and cellular roles of phosphoinositide 5-kinases. , 2004, European journal of pharmacology.

[21]  A. Staruschenko,et al.  Ras Activates the Epithelial Na+ Channel through Phosphoinositide 3-OH Kinase Signaling* , 2004, Journal of Biological Chemistry.

[22]  B. Ache,et al.  Modulation of the Olfactory CNG Channel by Ptdlns(3,4,5)P3 , 2004, The Journal of Membrane Biology.

[23]  L. Malbert-Colas,et al.  A naturally occurring human Nedd4-2 variant displays impaired ENaC regulation in Xenopus laevis oocytes. , 2004, American journal of physiology. Renal physiology.

[24]  C. Erneux,et al.  Phosphatidylinositol 3,4,5-trisphosphate: an early mediator of insulin-stimulated sodium transport in A6 cells. , 2004, American journal of physiology. Renal physiology.

[25]  J. Stockand,et al.  Regulation of Na+ transport by aldosterone: signaling convergence and cross talk between the PI3-K and MAPK1/2 cascades. , 2004, American journal of physiology. Renal physiology.

[26]  N. Gamper,et al.  Direct Activation of the Epithelial Na+ Channel by Phosphatidylinositol 3,4,5-Trisphosphate and Phosphatidylinositol 3,4-Bisphosphate Produced by Phosphoinositide 3-OH Kinase* , 2004, Journal of Biological Chemistry.

[27]  Richard C Boucher,et al.  Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice , 2004, Nature Medicine.

[28]  K. Kaibuchi,et al.  PIP3 is involved in neuronal polarization and axon formation , 2004, Journal of neurochemistry.

[29]  K. Jakobs,et al.  Activation of Type I Phosphatidylinositol 4-Phosphate 5-Kinase Isoforms by the Rho GTPases, RhoA, Rac1, and Cdc42* , 2004, Journal of Biological Chemistry.

[30]  P. Snyder,et al.  A Region Directly Following the Second Transmembrane Domain in γENaC Is Required for Normal Channel Gating* , 2003, Journal of Biological Chemistry.

[31]  Jian Yang,et al.  Localization of PIP2 activation gate in inward rectifier K+ channels , 2003, Nature Neuroscience.

[32]  R. Anderson,et al.  Phosphatidylinositol Phosphate Kinases Put PI4,5P2 in Its Place , 2003, The Journal of Membrane Biology.

[33]  E. Behr,et al.  PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome , 2003, Neurology.

[34]  D. Julius,et al.  A Modular PIP2 Binding Site as a Determinant of Capsaicin Receptor Sensitivity , 2003, Science.

[35]  R. Firtel,et al.  Receptor-mediated regulation of PI3Ks confines PI(3,4,5)P3 to the leading edge of chemotaxing cells. , 2003, Molecular biology of the cell.

[36]  Z. Molnár,et al.  Specificity of activation by phosphoinositides determines lipid regulation of Kir channels , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[37]  K. Dong,et al.  Localization of the ATP/Phosphatidylinositol 4,5 Diphosphate-binding Site to a 39-Amino Acid Region of the Carboxyl Terminus of the ATP-regulated K+ Channel Kir1.1* , 2002, The Journal of Biological Chemistry.

[38]  Jian Yang,et al.  Dual regulation of voltage-gated calcium channels by PtdIns(4,5)P2 , 2002, Nature.

[39]  J. Stockand,et al.  Activation of mitogen-activated protein kinase (mitogen-activated protein kinase/extracellular signal-regulated kinase) cascade by aldosterone. , 2002, Molecular biology of the cell.

[40]  Arya M. Sharma,et al.  Serum- and Glucocorticoid-Regulated Kinase (SGK1) Gene and Blood Pressure , 2002, Hypertension.

[41]  E. Kamynina,et al.  Concerted action of ENaC, Nedd4-2, and Sgk1 in transepithelial Na(+) transport. , 2002, American journal of physiology. Renal physiology.

[42]  B. Hille,et al.  Recovery from Muscarinic Modulation of M Current Channels Requires Phosphatidylinositol 4,5-Bisphosphate Synthesis , 2002, Neuron.

[43]  Jian Yang,et al.  Alterations in Conserved Kir Channel-PIP2 Interactions Underlie Channelopathies , 2002, Neuron.

[44]  D. Eaton,et al.  Phosphatidylinositol 4,5-Bisphosphate (PIP2) Stimulates Epithelial Sodium Channel Activity in A6 Cells* , 2002, The Journal of Biological Chemistry.

[45]  P. Snyder The epithelial Na+ channel: cell surface insertion and retrieval in Na+ homeostasis and hypertension. , 2002, Endocrine reviews.

[46]  J. Stockand New ideas about aldosterone signaling in epithelia. , 2002, American journal of physiology. Renal physiology.

[47]  D. Warnock,et al.  Anionic Phospholipids Regulate Native and Expressed Epithelial Sodium Channel (ENaC)* , 2002, The Journal of Biological Chemistry.

[48]  G. Giebisch,et al.  Nucleotides and phospholipids compete for binding to the C terminus of KATP channels , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[49]  Simeon I. Taylor,et al.  sgk: an essential convergence point for peptide and steroid hormone regulation of ENaC-mediated Na+ transport. , 2002, American journal of physiology. Cell physiology.

[50]  B. Ache,et al.  3-Phosphoinositides Modulate Cyclic Nucleotide Signaling in Olfactory Receptor Neurons , 2002, Neuron.

[51]  D. Hilgemann,et al.  Nonradioactive analysis of phosphatidylinositides and other anionic phospholipids by anion-exchange high-performance liquid chromatography with suppressed conductivity detection. , 2002, Analytical biochemistry.

[52]  L. Schild,et al.  Epithelial sodium channel/degenerin family of ion channels: a variety of functions for a shared structure. , 2002, Physiological reviews.

[53]  P. Snyder,et al.  Serum and Glucocorticoid-regulated Kinase Modulates Nedd4-2-mediated Inhibition of the Epithelial Na+Channel* , 2002, The Journal of Biological Chemistry.

[54]  David Pearce,et al.  Phosphorylation of Nedd4‐2 by Sgk1 regulates epithelial Na+ channel cell surface expression , 2001, The EMBO journal.

[55]  D. Hilgemann,et al.  The Complex and Intriguing Lives of PIP2 with Ion Channels and Transporters , 2001, Science's STKE.

[56]  P. Cullen,et al.  Modular phosphoinositide-binding domains – their role in signalling and membrane trafficking , 2001, Current Biology.

[57]  L. Schild,et al.  Trafficking and cell surface stability of ENaC. , 2001, American journal of physiology. Renal physiology.

[58]  S. Emr,et al.  The role of phosphoinositides in membrane transport. , 2001, Current opinion in cell biology.

[59]  A. Basbaum,et al.  Bradykinin and nerve growth factor release the capsaicin receptor from PtdIns(4,5)P2-mediated inhibition , 2001, Nature.

[60]  S. Subramony,et al.  Mutations in Kir2.1 Cause the Developmental and Episodic Electrical Phenotypes of Andersen's Syndrome , 2001, Cell.

[61]  D. Bar-Sagi A Ras by Any Other Name , 2001, Molecular and Cellular Biology.

[62]  Ali G. Gharavi,et al.  Molecular Mechanisms of Human Hypertension , 2001, Cell.

[63]  S. Heinemann,et al.  Multiple PIP2 binding sites in Kir2.1 inwardly rectifying potassium channels , 2001, FEBS letters.

[64]  P. Barbry,et al.  SGK integrates insulin and mineralocorticoid regulation of epithelial sodium transport. , 2001, American journal of physiology. Renal physiology.

[65]  C. Nichols,et al.  Structural Determinants of Pip2 Regulation of Inward Rectifier KATP Channels , 2000, The Journal of general physiology.

[66]  E. Kobrinsky,et al.  Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+-current desensitization , 2000, Nature Cell Biology.

[67]  B. Blazer-Yost,et al.  LY-294002-inhibitable PI 3-kinase and regulation of baseline rates of Na(+) transport in A6 epithelia. , 2000, American journal of physiology. Cell physiology.

[68]  K. Jakobs,et al.  Stimulation of Phosphatidylinositol-4-phosphate 5-Kinase by Rho-Kinase* , 2000, The Journal of Biological Chemistry.

[69]  J. Ruppersberg,et al.  pH gating of ROMK (K(ir)1.1) channels: control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[70]  G. Prestwich,et al.  Distinct Specificities of Inwardly Rectifying K+Channels for Phosphoinositides* , 1999, The Journal of Biological Chemistry.

[71]  D. Eaton,et al.  Regulation of Na+ Reabsorption by the Aldosterone-induced Small G Protein K-Ras2A* , 1999, The Journal of Biological Chemistry.

[72]  John P. Johnson,et al.  Vasopressin stimulates sodium transport in A6 cells via a phosphatidylinositide 3-kinase-dependent pathway. , 1999, American journal of physiology. Renal physiology.

[73]  B. Blazer-Yost,et al.  Phosphoinositide 3-kinase is required for aldosterone-regulated sodium reabsorption. , 1999, American journal of physiology. Cell physiology.

[74]  Michele Pagano,et al.  SKP2 is required for ubiquitin-mediated degradation of the CDK inhibitor p27 , 1999, Nature Cell Biology.

[75]  Cheng He,et al.  Activation of inwardly rectifying K+ channels by distinct PtdIns(4,5)P2 interactions , 1999, Nature Cell Biology.

[76]  A. Náray-Fejes-Tóth,et al.  sgk Is an Aldosterone-induced Kinase in the Renal Collecting Duct , 1999, The Journal of Biological Chemistry.

[77]  F. Verrey,et al.  Aldosterone action: induction of p21 ras and fra-2 and transcription-independent decrease in myc, jun, and fos. , 1999, American journal of physiology. Cell physiology.

[78]  O. Meijer,et al.  Epithelial sodium channel regulated by aldosterone-induced protein sgk. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[79]  L. Schild,et al.  Defective regulation of the epithelial Na+ channel by Nedd4 in Liddle's syndrome. , 1999, The Journal of clinical investigation.

[80]  E. Hummler,et al.  V. The epithelial sodium channel and its implication in human diseases. , 1999, American journal of physiology. Gastrointestinal and liver physiology.

[81]  J. Loffing,et al.  Ras pathway activates epithelial Na+ channel and decreases its surface expression in Xenopus oocytes. , 1998, Molecular biology of the cell.

[82]  C. M. Adams,et al.  Inhibition of the Epithelial Na+ Channel by Interaction of Nedd4 with a PY Motif Deleted in Liddle’s Syndrome* , 1998, The Journal of Biological Chemistry.

[83]  C. Canessa,et al.  Subunit Composition Determines the Single Channel Kinetics of the Epithelial Sodium Channel , 1998, The Journal of general physiology.

[84]  B. Blazer-Yost,et al.  Phosphatidylinositol 3-kinase activation is required for insulin-stimulated sodium transport in A6 cells. , 1998, American journal of physiology. Endocrinology and metabolism.

[85]  O. Staub,et al.  Regulation of stability and function of the epithelial Na+ channel (ENaC) by ubiquitination , 1997, The EMBO journal.

[86]  F. Verrey,et al.  Characterization of early aldosterone-induced RNAs identified in A6 kidney epithelia , 1997, Pflügers Archiv.

[87]  P. Warne,et al.  Role of Phosphoinositide 3-OH Kinase in Cell Transformation and Control of the Actin Cytoskeleton by Ras , 1997, Cell.

[88]  H. Garty,et al.  Epithelial sodium channels: function, structure, and regulation. , 1997, Physiological reviews.

[89]  D. Hilgemann,et al.  Regulation of Cardiac Na+,Ca2+ Exchange and KATP Potassium Channels by PIP2 , 1996, Science.

[90]  O. Staub,et al.  WW domains of Nedd4 bind to the proline‐rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome. , 1996, The EMBO journal.

[91]  C. M. Adams,et al.  Mechanism by which Liddle's syndrome mutations increase activity of a human epithelial Na+ channel , 1995, Cell.

[92]  F. Verrey Transcriptional control of sodium transport in tight epithelia by adrenal steroids , 1995, The Journal of Membrane Biology.

[93]  L. Schild,et al.  Amiloride-sensitive epithelial Na+ channel is made of three homologous subunits , 1994, Nature.

[94]  B. Rossier,et al.  Epithelial sodium channel related to proteins involved in neurodegeneration , 1993, Nature.

[95]  J. Stockand,et al.  Receptor tyrosine kinases mediate epithelial Na(+) channel inhibition by epidermal growth factor. , 2005, American journal of physiology. Renal physiology.

[96]  J. Floros,et al.  SP-A1 and SP-A2 variants differentially enhance association of Pseudomonas aeruginosa with rat alveolar macrophages. , 2005, American journal of physiology. Lung cellular and molecular physiology.

[97]  Jason M Haugh,et al.  Spatial analysis of 3' phosphoinositide signaling in living fibroblasts: II. Parameter estimates for individual cells from experiments. , 2004, Biophysical journal.