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Bernard C. Rossier - One of the best experts on this subject based on the ideXlab platform.

  • Epithelial Sodium Channel enac and the control of blood pressure
    Current Opinion in Pharmacology, 2014
    Co-Authors: Bernard C. Rossier
    Abstract:

    The amiloride-sensitive Epithelial Sodium Channel (ENaC) constitutes the rate-limiting step for Sodium reabsorption in Epithelial cells that line the distal part of the renal tubule, the distal colon, the duct of several exocrine glands, and the lung. The activity of this Channel is regulated by aldosterone and hormones involved in the maintenance of Sodium balance, blood volume and blood pressure. In this review, we discuss recent advances in our understanding of ENaC function and regulation relevant to the control of Sodium balance and blood pressure. The identification of novel drug targets should help in the development of the next generation of diuretics and of new therapies for the treatment of hypertension.

  • The Epithelial Sodium Channel
    2012
    Co-Authors: Bernard C. Rossier
    Abstract:

    The Epithelial Sodium Channel (ENaC) was cloned just 10 years ago. Since that time, the study of human monogenic diseases (pseudohypoaldosteronism type 1 [PHA-1] and Liddle syndrome), as well as mouse models mimicking salt-losing syndromes (PHA-1) or salt-sensitive hypertension (Liddle syndrome), have greatly contributed to our understanding of the function of ENaC in vivo. In this brief review, I will first discuss ENaC as a limiting factor in the control of ionic composition of the extracellular fluid and then, more specifically, the activation of ENaC by membrane-bound serine proteases. Recent in vitro and in vivo experiments indicate that membrane-bound serine proteases (Channel activating proteases [CAP-1, -2, or-3]) may be of critical importance in the activation of ENaC in different organs, such as the kidney, the lung or the cochlea.

  • activation of the Epithelial Sodium Channel enac by serine proteases
    Annual Review of Physiology, 2009
    Co-Authors: Bernard C. Rossier, Jackson M Stutts
    Abstract:

    The study of human monogenic diseases [pseudohypoaldosteronism type 1 (PHA-1) and Liddle's syndrome] as well as mouse models mimicking the salt-losing syndrome (PHA-1) or salt-sensitive hypertension (Liddle's syndrome) have established the Epithelial Sodium Channel ENaC as a limiting factor in vivo in the control of ionic composition of the extracellular fluid, regulation of blood volume and blood pressure, lung alveolar clearance, and airway mucociliary clearance. In this review, we discuss more specifically the activation of ENaC by serine proteases. Recent in vitro and in vivo experiments indicate that membrane-bound serine proteases are of critical importance in the activation of ENaC in different organs, such as the kidney, the lung, or the cochlea. Progress in understanding the basic mechanism of proteolytic activation of ENaC is accelerating, but uncertainty about the most fundamental aspects persists, leaving numerous still-unanswered questions.

  • Renal Sodium Handling: The Role of the Epithelial Sodium Channel
    Journal of The American Society of Nephrology, 2005
    Co-Authors: David G. Warnock, Bernard C. Rossier
    Abstract:

    The Epithelial Sodium Channel (ENaC) is a critically important final regulator of the balance between intake and excretion of dietary Sodium ([1][1]), and along with the thiazide-sensitive NaCl co-transporter constitutes the predominant Sodium transport systems in the aldosterone-sensitive distal

  • The Epithelial Sodium Channel: activation by membrane-bound serine proteases.
    Proceedings of the American Thoracic Society, 2004
    Co-Authors: Bernard C. Rossier
    Abstract:

    The Epithelial Sodium Channel (ENaC) was cloned just 10 years ago. Since that time, the study of human monogenic diseases (pseudohypoaldosteronism type 1 [PHA-1] and Liddle syndrome), as well as mouse models mimicking salt-losing syndromes (PHA-1) or salt-sensitive hypertension (Liddle syndrome), have greatly contributed to our understanding of the function of ENaC in vivo. In this brief review, I will first discuss ENaC as a limiting factor in the control of ionic composition of the extracellular fluid and then, more specifically, the activation of ENaC by membrane-bound serine proteases. Recent in vitro and in vivo experiments indicate that membrane-bound serine proteases (Channel activating proteases [CAP-1, -2, or-3]) may be of critical importance in the activation of ENaC in different organs, such as the kidney, the lung or the cochlea.

Cecilia M. Canessa - One of the best experts on this subject based on the ideXlab platform.

  • Role of SGK in hormonal regulation of Epithelial Sodium Channel in A6 cells.
    American Journal of Physiology-cell Physiology, 2002
    Co-Authors: Diego Alvarez De La Rosa, Cecilia M. Canessa
    Abstract:

    The purpose of this study was to examine the role of the serum- and glucocorticoid-induced kinase (SGK) in the activation of the Epithelial Sodium Channel (ENaC) by aldosterone, arginine vasopressi...

  • Heterologous expression of a mammalian Epithelial Sodium Channel in yeast
    FEBS Letters, 2000
    Co-Authors: Soma Sen Gupta, Cecilia M. Canessa
    Abstract:

    The α and β subunits of the amiloride-sensitive rat Epithelial Sodium Channel (αβENaC) were expressed in the yeast Saccharomyces cerevisiae. We used a combination of yeast strains, including a mutant in the secretory pathway (sec6), and Western blotting techniques, to show that αβENaC was synthesized and targeted through the secretory system to the plasma membrane. Yeasts expressing αβENaC were more sensitive to salt than the parent strain. In addition, amiloride, a specific blocker of ENaC, was found to suppress salt sensitivity in the yeast strain expressing αβENaC.

  • in vivo phosphorylation of the Epithelial Sodium Channel
    Proceedings of the National Academy of Sciences of the United States of America, 1998
    Co-Authors: Richard A. Shimkets, Richard P Lifton, Cecilia M. Canessa
    Abstract:

    The activity of the Epithelial Sodium Channel (ENaC) in the distal nephron is regulated by an antidiuretic hormone, aldosterone, and insulin, but the molecular mechanisms that mediate these hormonal effects are mostly unknown. We have investigated whether aldosterone, insulin, or activation of protein kinases has an effect on the phosphorylation of the Channel. Experiments were performed in an Epithelial cell line generated by stable cotransfection of the three subunits (α, β, and γ) of ENaC. We found that β and γ, but not the α subunit, are phosphorylated in the basal state. Aldosterone, insulin, and protein kinases A and C increased phosphorylation of the β and γ subunits in their carboxyl termini, but none of these agents induced de novo phosphorylation of α subunits. Serines and threonines but not tyrosines were found to be phosphorylated. The results suggest that aldosterone, insulin, and protein kinases A and C modulate the activity of ENaC by phosphorylation of the carboxyl termini of the β and γ subunits.

  • Expression cloning of the Epithelial Sodium Channel
    Kidney International, 1995
    Co-Authors: Cecilia M. Canessa, Jean-daniel Horisberger, Laurent Schild, Bernard C. Rossier
    Abstract:

    Complex organisms take Sodium from the external environment to achieve and maintain extracellular volume and blood pressure. Many Sodium transporter systems have evolved, and among them the Epithelial Sodium Channel plays a fundamental role in determining the final amount of Sodium reabsorbed. Epithelial Sodium Channels are present in the apical membrane of cells lining the distal segment of the nephron, urinary bladder, distal colon, and the airways. In the skin they are found in the sweat ducts and in certain animals (amphibians) they are also present in the epidermal cells. All these tissues absorb Sodium via an amiloride-sensitive, highly selective Na + Channel. This paper discusses recent efforts that have lead to the cloning and the elucidation of the structure of the Epithelial Sodium Channel.

  • membrane topology of the Epithelial Sodium Channel in intact cells
    American Journal of Physiology-cell Physiology, 1994
    Co-Authors: Cecilia M. Canessa, A M Merillat, Bernard C. Rossier
    Abstract:

    The highly selective amiloride-sensitive Epithelial Sodium Channel is formed of three homologous subunits termed alpha-, beta-, and gamma-rENaC. Each subunit has two putative transmembrane domains ...

Christoph Korbmacher - One of the best experts on this subject based on the ideXlab platform.

Peter M Snyder - One of the best experts on this subject based on the ideXlab platform.

  • extracellular chloride regulates the Epithelial Sodium Channel
    Journal of Biological Chemistry, 2009
    Co-Authors: Daniel M Collier, Peter M Snyder
    Abstract:

    Abstract The extracellular domain of the Epithelial Sodium Channel ENaC is exposed to a wide range of Cl− concentrations in the kidney and in other epithelia. We tested whether Cl− alters ENaC activity. In Xenopus oocytes expressing human ENaC, replacement of Cl− with SO42−, H2PO4−, or SCN− produced a large increase in ENaC current, indicating that extracellular Cl− inhibits ENaC. Extracellular Cl− also inhibited ENaC in Na+-transporting epithelia. The anion selectivity sequence was SCN− < SO42− < H2PO4− < F− < I− < Cl− < Br−. Crystallization of ASIC1a revealed a Cl− binding site in the extracellular domain. We found that mutation of corresponding residues in ENaC (αH418A and βR388A) disrupted the response to Cl−, suggesting that Cl− might regulate ENaC through an analogous binding site. Maneuvers that lock ENaC in an open state (a DEG mutation and trypsin) abolished ENaC regulation by Cl−. The response to Cl− was also modulated by changes in extracellular pH; acidic pH increased and alkaline pH reduced ENaC inhibition by Cl−. Cl− regulated ENaC activity in part through enhanced Na+ self-inhibition, a process by which extracellular Na+ inhibits ENaC. Together, the data indicate that extracellular Cl− regulates ENaC activity, providing a potential mechanism by which changes in extracellular Cl− might modulate Epithelial Na+ absorption.

  • number of subunits comprising the Epithelial Sodium Channel
    Journal of Biological Chemistry, 1999
    Co-Authors: Sepehr Eskandari, Peter M Snyder, Michael J Welsh, Michael Kreman, Guido A Zampighi, Ernest M Wright
    Abstract:

    Abstract The human Epithelial Sodium Channel (hENaC) is a hetero-oligomeric complex composed of three subunits, α, β, and γ. Understanding the structure and function of this Channel and its abnormal behavior in disease requires knowledge of the number of subunits that comprise the Channel complex. We used freeze-fracture electron microscopy and electrophysiological methods to evaluate the number of subunits in the ENaC complex expressed in Xenopus laevis oocytes. In oocytes expressing wild-type hENaC (α, β, and γ subunits), clusters of particles appeared in the protoplasmic face of the plasma membrane. The total number of particles in the clusters was consistent with the whole-cell amiloride-sensitive current measured in the same cells. The size frequency histogram for the particles in the clusters suggested the presence of an integral membrane protein complex composed of 17 ± 2 transmembrane α-helices. Because each ENaC subunit has two putative transmembrane helices, these data suggest that in the oocyte plasma membrane, the ENaC complex is composed of eight or nine subunits. At high magnification, individual ENaC particles exhibited a near-square geometry. Functional studies using wild-type αβ-hENaC coexpressed with γ-hENaC mutants, which rendered the functional Channel differentially sensitive to methanethiosulfonate reagents and cadmium, suggested that the functional Channel complex contains more than one γ subunit. These data suggest that functional ENaC consists of eight or nine subunits of which a minimum of two are γ subunits.

  • interactions between subunits of the human Epithelial Sodium Channel
    Journal of Biological Chemistry, 1997
    Co-Authors: Christopher M Adams, Peter M Snyder, Michael J Welsh
    Abstract:

    Abstract The human Epithelial Sodium Channel (hENaC) mediates Na+ transport across the apical membrane of epithelia, and mutations in hENaC result in hypertensive and salt-wasting diseases. In heterologous expression systems, maximal hENaC function requires co-expression of three homologous proteins, the α, β, and γhENaC subunits, suggesting that hENaC subunits interact to form a multimeric Channel complex. Using a co-immunoprecipitation assay, we found that hENaC subunits associated tightly to form homo- and heteromeric complexes and that the association between subunits occurred early in Channel biosynthesis. Deletion analysis of γhENaC revealed that the N terminus was sufficient but not necessary for co-precipitation of αhENaC, and that both the N terminus and the second transmembrane segment (M2) were required for γ subunit function. The biochemical studies were supported by functional studies. Co-expression of γ subunits lacking M2 with full-length hENaC subunits revealed an inhibitory effect on hENaC Channel function that appeared to be mediated by the cytoplasmic N terminus of γ, and was consistent with the assembly of nonfunctional subunits into the Channel complex. We conclude that the N terminus of γhENaC is involved in Channel assembly.

  • membrane topology of the amiloride sensitive Epithelial Sodium Channel
    Journal of Biological Chemistry, 1994
    Co-Authors: Peter M Snyder, Fiona J. Mcdonald, John B Stokes, Michael J Welsh
    Abstract:

    Abstract The amiloride-sensitive Epithelial Sodium Channel (ENaC) is involved in fluid and electrolyte absorption across a number of epithelia, and cloning of several ENaC subunits has begun to facilitate investigation of the structure, function, and regulation of this Channel. Analysis of the amino acid sequence has revealed two potential membrane-spanning domains, but little else is known about the structure of ENaC. To investigate the membrane topology of one subunit, alpha rENaC, we used in vitro transcription, translation, and translocation into microsomal membranes. This generated a glycosylated protein of 93 kDa. Sequence analysis also revealed eight potential sites for N-glycosylation, six of which were found to be glycosylated (Asn190, Asn259, Asn320, Asn339, Asn424, and Asn538), indicating that they are extracellular. The C terminus was localized as intracellular based on antibody recognition and protease sensitivity of a tagged epitope at the C terminus. The N terminus was also found to be intracellular, based on its protease sensitivity. Similar results were obtained by expression in Xenopus oocytes. Together, these results support a model of alpha rENaC consisting of an intracellular N terminus and C terminus, a large N-glycosylated extracellular domain, and two membrane-spanning domains that each pass once through the plasma membrane. Because of their sequence similarity, it is likely that this structure is shared by other ENaC subunits and possibly the degenerins of Caenorhabditis elegans as well.

Richard A. Shimkets - One of the best experts on this subject based on the ideXlab platform.

  • in vivo phosphorylation of the Epithelial Sodium Channel
    Proceedings of the National Academy of Sciences of the United States of America, 1998
    Co-Authors: Richard A. Shimkets, Richard P Lifton, Cecilia M. Canessa
    Abstract:

    The activity of the Epithelial Sodium Channel (ENaC) in the distal nephron is regulated by an antidiuretic hormone, aldosterone, and insulin, but the molecular mechanisms that mediate these hormonal effects are mostly unknown. We have investigated whether aldosterone, insulin, or activation of protein kinases has an effect on the phosphorylation of the Channel. Experiments were performed in an Epithelial cell line generated by stable cotransfection of the three subunits (α, β, and γ) of ENaC. We found that β and γ, but not the α subunit, are phosphorylated in the basal state. Aldosterone, insulin, and protein kinases A and C increased phosphorylation of the β and γ subunits in their carboxyl termini, but none of these agents induced de novo phosphorylation of α subunits. Serines and threonines but not tyrosines were found to be phosphorylated. The results suggest that aldosterone, insulin, and protein kinases A and C modulate the activity of ENaC by phosphorylation of the carboxyl termini of the β and γ subunits.

  • mutations in subunits of the Epithelial Sodium Channel cause salt wasting with hyperkalaemic acidosis pseudohypoaldosteronism type 1
    Nature Genetics, 1996
    Co-Authors: Laurent Schild, Aaron Hanukoglu, Stefan Gründer, Sue S Chang, Ariel Rosler, P M Mathew, Israel Hanukoglu, Yin Lu, Richard A. Shimkets
    Abstract:

    Autosomal recessive pseudohypoaldosteronism type I is a rare life-threatening disease characterized by severe neonatal salt wasting, hyperkalaemia, metabolic acidosis, and unresponsiveness to mineralocorticoid hormones. Investigation of affected offspring of consanguineous union reveals mutations in either the α or β subunits of the amiloride-sensitive Epithelial Sodium Channel in five kindreds. These mutations are homozygous in affected subjects, co-segregate with the disease, and introduce frameshift, premature termination or missense mutations that result in loss of Channel activity. These findings demonstrate the molecular basis and explain the pathophysiology of this disease

  • liddle s syndrome heritable human hypertension caused by mutations in the s subnit of the Epithelial Sodium Channel
    Journal of Endocrinological Investigation, 1995
    Co-Authors: Richard A. Shimkets, David G. Warnock, Christopher M. Bositis, Joni H. Hansson, Morris Schambelan, John R. Gill, Stanley Ulick, Robert V. Milora, Carol Nelsonwilliams, James W. Findling
    Abstract:

    Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings suggesting constitutive activation of the amiloride-sensitive distal renal Epithelial Sodium Channel. We demonstrate complete linkage of the gene encoding the β subunit of the Epithelial Sodium Channel to Liddle's syndrome in Liddle's original kindred. Analysis of this gene reveals a premature stop codon that truncates the cytoplasmic carboxyl terminus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates either premature termination or frameshift mutations in this same carboxy-terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the β subunit of the Epithelial Sodium Channel and have implications for the regulation of this Epithelial ion Channel as well as blood pressure homeostasis.

  • Liddle’s syndrome: Heritable human hypertension caused by mutations in the ß subnit of the Epithelial Sodium Channel
    Journal of Endocrinological Investigation, 1995
    Co-Authors: Richard A. Shimkets, David G. Warnock, Christopher M. Bositis, Carol Nelson-williams, Joni H. Hansson, Morris Schambelan, John R. Gill, Stanley Ulick, Robert V. Milora, James W. Findling
    Abstract:

    Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings suggesting constitutive activation of the amiloride-sensitive distal renal Epithelial Sodium Channel. We demonstrate complete linkage of the gene encoding the β subunit of the Epithelial Sodium Channel to Liddle's syndrome in Liddle's original kindred. Analysis of this gene reveals a premature stop codon that truncates the cytoplasmic carboxyl terminus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates either premature termination or frameshift mutations in this same carboxy-terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the β subunit of the Epithelial Sodium Channel and have implications for the regulation of this Epithelial ion Channel as well as blood pressure homeostasis.

  • liddle s syndrome heritable human hypertension caused by mutations in the β subunit of the Epithelial Sodium Channel
    Cell, 1994
    Co-Authors: Richard A. Shimkets, David G. Warnock, Christopher M. Bositis, Joni H. Hansson, Morris Schambelan, John R. Gill, Stanley Ulick, Robert V. Milora, Carol Nelsonwilliams, James W. Findling
    Abstract:

    Abstract Liddle's syndrome (pseudoaldosteronism) is an autosomal dominant form of human hypertension characterized by a constellation of findings suggesting constitutive activation of the amiloride-sensitive distal renal Epithelial Sodium Channel. We demonstrate complete linkage of the gene encoding the β subunit of the Epithelial Sodium Channel to Liddle's syndrome in Liddle's original kindred. Analysis of this gene reveals a premature stop codon that truncates the cytoplasmic carboxyl terminus of the encoded protein in affected subjects. Analysis of subjects with Liddle's syndrome from four additional kindreds demonstrates either premature termination or frameshift mutations in this same carboxy-terminal domain in all four. These findings demonstrate that Liddle's syndrome is caused by mutations in the β subunit of the Epithelial Sodium Channel and have implications for the regulation of this Epithelial ion Channel as well as blood pressure homeostasis.