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Sodium/hydrogen exchanger NHA2 - quest for biological function

English title Sodium/hydrogen exchanger NHA2 - quest for biological function
Applicant Fuster Daniel Guido
Number 135503
Funding scheme Project funding
Research institution Respiratory Medicine Department Universitätsklinik Inselspital
Institution of higher education University of Berne - BE
Main discipline Pathophysiology
Start/End 01.05.2011 - 30.04.2014
Approved amount 306'170.00
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All Disciplines (6)

Discipline
Pathophysiology
Biochemistry
Endocrinology
Physiology : other topics
Molecular Biology
Cellular Biology, Cytology

Keywords (1)

Membrane transport, sodium/hydrogen exchanger

Lay Summary (English)

Lead
Lay summary

Na+/H+ exchangers (NHEs) are ubiquitous ion transporters present in the cell membranes of bacterias, plants, fungi and animals. In mammals, 12 NHE isoforms have been cloned so far, including two recently cloned evolutionarily very conserved NHEs, named NHA1 and NHA2. NHA2 is expressed ubiquitously. However, within individual tissues, NHA2 is found only in a subset of specialized cells. Examples include osteoclasts in the bone,  distal tubular cells of the kidney or neurons in the brain. The biological role of NHA2 within these cells remains mostly obscure at the moment. Published studies and our preliminary data in NHA2-deficient mice highlight the importance of NHA2 for osteoclast development and function. Based on expression pattern, transport characteristics and genomic localization, NHA2 most likely represents the long sought Na+/Li+ countertransporter that was linked to the pathogenesis of diabetes mellitus and arterial hypertension in retro- and prospective studies.

Given current evidence, we hypothesize that mammalian NHA2 plays a vital role in bone turnover and regulation of blood pressure.

It is the goal of this proposal to rigorously test the above mentioned hypotheses, thereby exploring the biological role of NHA2. This will be achieved by a multidisciplinary approach as follows:

 

 

  1. Detailed phenotype characterization of NHA2 knock-out mice.
  2. Study of NHA2 kinetics by use of whole-cell patch-clamp combined with ion-selective electrodes in mammalian cells.
  3. Search for NHA2-associated proteins.
  4. Genetic and functional analysis of NHA2 variants in a large database of well characterized patients with essential hypertension and in an age- and sex-matched control population.

We are convinced that, in the light of our promising preliminary data and multifaceted approach, our proposal will have a high chance of success in elucidating the biological role of NHA2 in mammalian biology. Research on NHA2 will likely shed light on the pathogenesis of arterial hypertension, diabetes mellitus and osteoporosis, diseases, which pose a major burden to our society.


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice.
Deisl Christine, Anderegg Manuel, Albano Giuseppe, Lüscher Benjamin, Cerny David, Soria Rodrigo, Bouillet Elisa, Rimoldi Stefano, Scherrer Urs, Fuster Daniel (2016), Loss of Sodium/Hydrogen Exchanger NHA2 Exacerbates Obesity- and Aging-Induced Glucose Intolerance in Mice., in Plos one, e0163568.
Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria
Dhayat N., Simonin A., Anderegg M., Pathare G., Lu scher B. P., Deisl C., Albano G., Mordasini D., Hediger M. A., Surbek D. V., Vogt B., Sass J. O., Kloeckener-Gruissem B., Fuster D. G. (2016), Mutation in the Monocarboxylate Transporter 12 Gene Affects Guanidinoacetate Excretion but Does Not Cause Glucosuria, in Journal of the American Society of Nephrology, 27(5), 1426-1436.
The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers
Dhayat Nasser, Schaller Andre, Albano Giuseppe, Poindexter John, Griffith Carolyn, Pasch Andreas, Gallati Sabina, Vogt Bruno, Moe Orson, Daniel Fuster (2016), The Vacuolar H+-ATPase B1 Subunit Polymorphism p.E161K Associates with Impaired Urinary Acidification in Recurrent Stone Formers, in JASN, 1544-1554.
Sodium-Dependent Phosphate Transporters in Osteoclast Differentiation and Function
Albano Giuseppe, Moor Matthias, Dolder Silvia, Siegrist Mark, Wagner Carsten A., Biber Jürg, Hernando Nati, Hofstetter Willy, Bonny Olivier, Fuster Daniel G. (2015), Sodium-Dependent Phosphate Transporters in Osteoclast Differentiation and Function, in PLOS ONE, 10(4), e0125104-e0125104.
Traditional and emerging roles for the SLC9 Na+/H+ exchangers
Fuster Daniel, Alexander Todd (2014), Traditional and emerging roles for the SLC9 Na+/H+ exchangers, in Pfluger Arch, 466(1), 61-76.
SLC9/NHE gene family, a plasma membrane and organellar family of Na +/H+ exchangers
Donowitz M, Ming Tse C, Fuster D (2013), SLC9/NHE gene family, a plasma membrane and organellar family of Na +/H+ exchangers, in Molecular Aspects of Medicine, 34(2-3), 236-251.
Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in β-cells.
Deisl Christine, Simonin Alexandre, Anderegg Manuel, Albano Giuseppe, Kovacs Gergely, Ackermann Daniel, Moch Holger, Dolci Wanda, Thorens Bernard, A Hediger Matthias, Fuster Daniel G (2013), Sodium/hydrogen exchanger NHA2 is critical for insulin secretion in β-cells., in Proceedings of the National Academy of Sciences of the United States of America, 110(24), 10004-9.
Gangrene and osteolysis in pancreatic insufficiency
Arampatzis S, Fuster DG (2012), Gangrene and osteolysis in pancreatic insufficiency, in Kidney International, 82(3), 364-364.
Dopamine inhibits the Na+/H+ Exchanger NHE3 via Protein Phosphatase 2A
Bobulescu Ion Alexandru, Quinones Henry, Gisler Serge M., Di Sole Francesca, Shi Mingjun, Hu Ming-Chang, Zhang Jianning, Fuster Daniel, Mumby Marc, Moe Orson (2011), Dopamine inhibits the Na+/H+ Exchanger NHE3 via Protein Phosphatase 2A, in Am J Physiol Renal Physiol, 24(298(5)), F1205-F1213.
Nedd4-1 and beta-Arrestin-1 Are Key Regulators of Na+/H+ Exchanger 1 Ubiquitylation, Endocytosis, and Function
Simonin Alexandre, Fuster Daniel (2011), Nedd4-1 and beta-Arrestin-1 Are Key Regulators of Na+/H+ Exchanger 1 Ubiquitylation, Endocytosis, and Function, in JOURNAL OF BIOLOGICAL CHEMISTRY, 285(49), 38293-38303.
Sodium/hydrogen exchanger NHA2 in osteoclasts: Subcellular localization and role in vitro and in vivo
Hofstetter Willy, Siegrist Mark, Simonin Alexandre, Bonny Olivier, Fuster Daniel G. (2011), Sodium/hydrogen exchanger NHA2 in osteoclasts: Subcellular localization and role in vitro and in vivo, in BONE, 47(2), 331-340.
Role of Na/H exchange in insulin secretion by islet cells
Deisl Christine, Albano Giuseppe, Fuster Daniel, Role of Na/H exchange in insulin secretion by islet cells, in Curr Opin Nephrol Hypertens, Epub ahead of print, Epub ahead.

Collaboration

Group / person Country
Types of collaboration
Max Planck Institut Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Universität Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Johns Hopkins School of Medicine United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
UT Southwestern Medical Center United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Universität Lausanne Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Einstein College of Medicine, Bronx, NY United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Invited lecture at Max Planck Institute Individual talk Physiological role of the sodium/hydrogen exchanger NHA2 30.01.2014 Frankfurt, Germany Fuster Daniel Guido;
Annual Meeting of the Swiss Society of Nephrology Talk given at a conference Role of the sodium/proton exchanger NHA2 in the kidney 04.12.2013 Schweiz, Switzerland Albano Giuseppe; Deisl Christine; Fuster Daniel Guido;
Biomedical Transporter Meeting Poster 2 Posters: 1) Role of NHA2 in the kidney and 2) Role of NHA2 in the endocrine pancreas. 1 Talk (Christine Deisl): Role of the sodium/proton exchagner NHA2 in the endocrine pancreas 11.08.2013 St. Moritz, Switzerland Deisl Christine; Fuster Daniel Guido; Albano Giuseppe;
Excellence in Women's Science Individual talk Role of the sodium/proton exchanger NHA2 in the endocrine pancreas 31.05.2013 Universität Bern, Switzerland Fuster Daniel Guido; Deisl Christine;
Renal physiology meeting Talk given at a conference Role of the sodium/proton exchanger NHA2 in blood pressure homeostasis and electrolyte handling 29.03.2013 Paris, Frankreich, France Fuster Daniel Guido;
Tag der klinischen Forschung Poster The sodium/proton exchanger NHA2 is critical for insulin secretion in beta-cells 06.11.2012 Inselspital Bern, Switzerland Deisl Christine; Fuster Daniel Guido;
Tag der klinischen Forschung Poster Role of the sodium/proton echanger in the endocrine pancreas 02.11.2011 Bern, Switzerland Deisl Christine; Fuster Daniel Guido;
ASN Meeting Philadelphia Individual talk NHA2 in osteoclasts: Subcellular localization and role in vitro and in vivo 26.10.2011 Philadelphia, United States of America Fuster Daniel Guido;


Communication with the public

Communication Title Media Place Year
New media (web, blogs, podcasts, news feeds etc.) Offizieller Newsrelease zu PNAS paper Verbreitet via online und Printmedien Western Switzerland German-speaking Switzerland Rhaeto-Romanic Switzerland International Italian-speaking Switzerland 2013

Associated projects

Number Title Start Funding scheme
117732 Elucidation of the pathways leading to inactivation and degradation of the sodium / hydrogen exchanger isoform 1 (NHE1) 01.01.2008 Project funding
172974 Mechanisms of thiazide-induced glucose intolerance 01.05.2017 Project funding
152829 Physiological role of the sodium/hydrogen exchanger NHE6 01.05.2014 Project funding
152829 Physiological role of the sodium/hydrogen exchanger NHE6 01.05.2014 Project funding

Abstract

Na+/H+ exchangers (NHEs) are ubiquitous ion transporters present in lipid bilayers in simple prokaryotes and eukaryotes, including plants, fungi and animals which harness the electrochemical gradient of one ion to energize the uphill transport of the other. In mammals, 12 NHE isoforms have been cloned so far, including plasmalemmal NHE1-5, intracellular NHE6-9, a sperm specific plasmalemmal NHE and two recently cloned evolutionarily very conserved NHEs, named NHA1 and NHA2 (or alternatively NHEDC1 and NHEDC2, respectively). NHAs belong to a new family of conserved metazoan NHEs that resemble more prokaryotic NHEs than the currently known eukaryotic NHEs. While NHA1 seems to be a gonad specific protein, NHA2 is expressed ubiquitously. However, within individual tissues, NHA2 is found only in a subset of specialized cells. Examples include osteoclasts in the bone, insulin secreting ß-cells of the pancreas, distal tubular cells of the kidney, neurons in the brain or chromaffine cells of the adrenal medulla. Based on the expression pattern, transport characteristics and genomic localization, NHA2 most likely represents the long sought Na+/Li+ countertransporter that was linked to the pathogenesis of diabetes mellitus and arterial hypertension in retro- and prospective studies. Currently, however, NHA2 kinetics as well as the biological role of NHA2 remain obscure.Based on published studies and our preliminary data, we hypothesize that mammalian NHA2 is a bona fide NHE that plays an important role in insulin secretion, renal Na+, Ca++ and acid-base homeostasis, blood pressure regulation as well as possibly bone turnover. It is the goal of this proposal to rigorously test the above mentioned hypotheses, thereby exploring the biological role of NHA2. This will be achieved by a multidisciplinary approach as follows:1.In vivo: Detailed phenotype characterization of NHA2 knock-out mice with focus on bone, endocrine pancreas, kidney and blood pressure regulation.2.In vitro: Extension of in vivo animal studies through analysis of the biological function of NHA2 on a cellular and molecular level. 3.Detailed characterization of NHA2 kinetics with fluorometry-based techniques and electrophysiological assays in different expression systems.We are convinced that, in the light of our promising preliminary data and multifaceted approach, our proposal will have a high chance of success in de-orphanizing NHA2 and elucidating its role in mammalian biology. Research on NHA2 will likely shed light on the pathogenesis of arterial hypertension, diabetes mellitus and osteoporosis, diseases, which pose a major burden to our society.
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