Project

Back to overview

Store-operated calcium channels in health and disease

English title Store-operated calcium channels in health and disease
Applicant Hediger Matthias A.
Number 160782
Funding scheme Sinergia
Research institution Institut für Biochemie und Molekulare Medizin Universität Bern
Institution of higher education University of Berne - BE
Main discipline Molecular Biology
Start/End 01.10.2015 - 30.09.2018
Approved amount 1'667'666.17
Show all

All Disciplines (9)

Discipline
Molecular Biology
Pharmacology, Pharmacy
Physiology : other topics
Cellular Biology, Cytology
Biochemistry
Pathophysiology
Organic Chemistry
Biophysics
Immunology, Immunopathology

Keywords (9)

Skeletal muscle dysfunction; Store-operated calcium entry; Immunology; SOCE; TRP channel; Calcium; Cancer; Calcium channel; Immune system

Lay Summary (German)

Lead
Ein Team von Wissenschaftlern an den Universitäten Bern und Genf mit Expertisen in den Fachgebieten Molekularbiologie, Physiologie und Chemie setzt sich zum Ziel, die detaillierten Funktionsmechanismen von „Store-Operated Calcium Entry“ (SOCE) aufzudecken, um damit verbundene menschliche Erkrankungen besser verstehen zu können.
Lay summary

Speicher-aktivierte Calciumkanäle im gesunden Körper und bei Krankheiten 

Inhalt und Ziele des Forschungsprojekts

Calcium ist für die Funktion des menschlichen Körpers ein essentieller Mineralstoff. Neben seiner bekannten Funktion im Aufbau von Knochen spielt Calcium zudem eine wichtige Rolle als Signalmolekül innerhalb einer jeden Zelle wie auch für die Funktion des gesamten Organismus. Die Calciumkanäle Orai 1-3 ermöglichen das Wiederauffüllen intrazellulärer Calciumspeicher nach deren Entleerung, z.B. aufgrund der Stimulation von Rezeptoren in der Zellmembran. Dieser Vorgang wird als «SOCE» (store-operated calcium entry) bezeichnet. Die Untersuchung der molekularen Mechanismen dieser Vorgänge ist von grosser klinischer Bedeutung, da diverse menschliche Erkrankungen damit verbunden sind. Wir haben hierfür eine interdisziplinäre Zusammenarbeit aufgebaut, um grundlegende Erkenntnisse in diesem Forschungsbereich zu gewinnen. Darauf aufbauend können in der Zukunft neuartige therapeutische Strategien entwickelt werden, welche die Funktionsweise von SOCE gezielt beeinflussen.

Unser Ansatz ermöglichte es uns, die Komplexität verschiedener Aspekte der SOCE- Signalübertragung im Detail zu verstehen. Wir konnten Isoform-spezifische Modulatoren der Orai1- und Orai3-Kanäle synthetisieren, welche die Ermittlung der Funktionsweise von Orai-Kanälen ermöglichen. Diese müssen durch Calcium-abhängige sogenannte «STIM-Proteine» des endoplasmatischen Retikulums innerhalb der Zellen geöffnet werden. Genetische Mutationen dieser Kanäle wurden in Patienten mit der Muskelkrankheit «Myopathie mit tubulären Aggregaten» identifiziert. Diese bewirken, dass sich die Orai-Kanäle unabhängig von STIM-Proteinen öffnen, was zu einer übermäßigen Calcium-Aufnahme der Muskelzellen und somit zu Schmerzen, Schwäche und Krämpfen der Muskeln führt. Wir konnten nun zeigen, wie genau diese Mutationen die Eigenschaften der Kanäle verändern, was den Verlauf der Muskelkrankheit erklärt. Wir haben auch die Wirkung des kommerziell erhältlichen Orai1 Inhibitors GSK7975A auf mehrere solche Orai-Mutationen charakterisiert und gezeigt, dass dieser die mutierten Kanäle der Patienten wirksam blockieren kann und somit im Prinzip als Medikament geeignet wäre. Wir haben auch gezeigt, dass STIM1, zusammen mit dem Interaktionspartner «UNC93B1» eine wichtige Rolle spielt bei angeborener Immunität gegen intrazelluläre Pathogene, Viren und Krebszellen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojektes

Wir erwarten, dass die Ergebnisse dieses Projektes relevant sein werden für eine gezieltere medikamentöse Behandlung menschlicher Erkrankungen in Bereichen des Immunsystems, der Muskelfunktion und bei Krebs.

Direct link to Lay Summary Last update: 09.11.2018

Responsible applicant and co-applicants

Employees

Publications

Publication
ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain
Bulla M., Gyimesi G., Kim JH., Bhardwaj R., Hediger M.A., Frieden M., Demaurex N. (2018), ORAI1 channel gating and selectivity is differentially altered by natural mutations in the first or third transmembrane domain, in The Journal of Physiology, 1.
The role of STIM proteins in neutrophil functions
Demaurex Nicolas, Saul Stephanie (2018), The role of STIM proteins in neutrophil functions, in The Journal of Physiology, 596(14), 2699-2708.
Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2.
Franz Marie C, Pujol-Giménez Jonai, Montalbetti Nicolas, Fernandez-Tenorio Miguel, DeGrado Timothy R, Niggli Ernst, Romero Michael F, Hediger Matthias A (2018), Reassessment of the Transport Mechanism of the Human Zinc Transporter SLC39A2., in Biochemistry, 57(26), 3976-3986.
GRAM marks the spot for STIM. Commentary on “GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells”
Nunes Paula, Demaurex Nicolas (2018), GRAM marks the spot for STIM. Commentary on “GRAM domain proteins specialize functionally distinct ER-PM contact sites in human cells”, in Cell Calcium, 73, 70-71.
STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells
Nunes-Hasler Paula, Maschalidi Sophia, Lippens Carla, Castelbou Cyril, Bouvet Samuel, Guido Daniele, Bermont Flavien, Bassoy Esen Y., Page Nicolas, Merkler Doron, Hugues Stéphanie, Martinvalet Denis, Manoury Bénédicte, Demaurex Nicolas (2017), STIM1 promotes migration, phagosomal maturation and antigen cross-presentation in dendritic cells, in Nature Communications, 8(1), 1852-1852.
UNC93B1 interacts with the calcium sensor STIM1 for efficient antigen cross-presentation in dendritic cells
Maschalidi Sophia, Nunes-Hasler Paula, Nascimento Clarissa R, Sallent Ignacio, Lannoy Valérie, Garfa-Traore Meriem, Cagnard Nicolas, Sepulveda Fernando E., Vargas Pablo, Lennon-Duménil Ana-Maria, van Endert Peter, Capiod Thierry, Demaurex Nicolas, Darrasse-Jèze Guillaume, Manoury Bénédicte (2017), UNC93B1 interacts with the calcium sensor STIM1 for efficient antigen cross-presentation in dendritic cells, in Nature Communications, 8(1), 1640-1640.
The ER phagosome connection in the era of membrane contact sites
Nunes-Hasler Paula, Demaurex Nicolas (2017), The ER phagosome connection in the era of membrane contact sites, in Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1864(9), 1513-1524.
ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate MyopathyHUMAN MUTATION
Böhm Johann, Bulla Monica, Urquhart Jill E., Malfatti Edoardo, Williams Simon G., O'Sullivan James, Szlauer Anastazja, Koch Catherine, Baranello Giovanni, Mora Marina, Ripolone Michela, Violano Raffaella, Moggio Maurizio, Kingston Helen, Dawson Timothy, DeGoede Christian G., Nixon John, Boland Anne, Deleuze Jean-François, Romero Norma, Newman William G., Demaurex Nicolas, Laporte Jocelyn (2017), ORAI1 Mutations with Distinct Channel Gating Defects in Tubular Aggregate MyopathyHUMAN MUTATION, in Human Mutation, (4), 426-438.
TRPV5 and TRPV6 Calcium-Selective Channels
Peng Ji-Bin, Suzuki Yoshiro, Gyimesi Gergely, Hediger Matthias A. (2017), TRPV5 and TRPV6 Calcium-Selective Channels, in Kozak Juliusz Ashot, Putney James W. (ed.), Productivity Press, Portland, 241-274.
The role of STIM and ORAI proteins in phagocytic immune cells
Demaurex Nicolas, Nunes Paula (2016), The role of STIM and ORAI proteins in phagocytic immune cells, in American Journal of Physiology - Cell Physiology, 310(7), C496-C508.
Redox modulation of STIM-ORAI signaling
Bhardwaj Rajesh, Hediger Matthias A., Demaurex Nicolas (2016), Redox modulation of STIM-ORAI signaling, in Cell Calcium, 60(2), 142-152.
Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method
Simonin Céline, Awale Mahendra, Brand Michael, van Deursen Ruud, Schwartz Julian, Fine Michael, Kovacs Gergely, Häfliger Pascal, Gyimesi Gergely, Sithampari Abilashan, Charles Roch-Philippe, Hediger Matthias A., Reymond Jean-Louis (2015), Optimization of TRPV6 Calcium Channel Inhibitors Using a 3D Ligand-Based Virtual Screening Method, in Angewandte Chemie International Edition, (49), 14748-14752.

Collaboration

Group / person Country
Types of collaboration
Univ.-Ass. Priv.-Doz. Dipl.-Ing. Dr.techn. Rainer Schindl Medizinische Universität Graz Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
PD Dr. Ivan Bogeski / Departement of Biophysics, Saarland University Faculty of Medicine Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Benedicte Manoury, INSERM, Paris France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christine Peinelt, IBMM, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Prof. Sven Rottenberg / Institute of Veterinary Pathology, University of Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
A. Univ.-Prof. Dr. Christoph Romanin, Johannes Kepler University Linz Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Ji-Bin Peng, University of Alabama at Birmingham United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Karl-Heinz Krause / Department of Pathology and Immunology, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Profs. Jocelyn Laporte, Johann Bohm / Institut de génétique et de biologie mol. et cell., Illkirch France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Jonathan Soboloff, Temple University United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Dr. Barbara Niemeyer Medizinische Fakultät der Universität des Saarlandes Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Pierre Cosson / Department of Cell Physiology and Metabolism, University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
2018 PhD retreat UNIGE Poster Ca2+ fluxes at membrane contact sites: does size matters? 03.10.2018 Leysin, Switzerland, Switzerland Henry Christopher; Demaurex Nicolas;
2018 EMBO workshop “Membrane Contact sites in Health and Disease” Poster Ca2+ fluxes at membrane contact sites: does size matters? 21.09.2018 Arosa, Switzerland Henry Christopher; Demaurex Nicolas;
2018 EMBO workshop “Membrane Contact sites in Health and Disease" Individual talk Regulation of cross-presentation by the SNARE Sec22b through ER-phagosome contact sites 21.09.2018 Arosa, Switzerland Demaurex Nicolas;
2018 EMBO workshop “Membrane Contact sites in Health and Disease” Poster Regulation of cross-presentation by the SNARE Sec22b through ER-phagosome membrane contact sites 21.09.2018 Arosa, Switzerland Demaurex Nicolas;
2018 International Meeting of the European Calcium Society Poster Cebpα-Cre-driven Stim1/Stim2 ablation to study store-operated Ca2+ entry in mouse neutrophils 09.09.2018 Hamburg, Germany Saul Stephanie; Fickentscher Céline; Demaurex Nicolas;
2018 International Meeting of the European Calcium Society Poster Regulation of Ca2+ fluxes at endoplasmic reticulum contact sites 09.09.2018 Hamburg, Germany Demaurex Nicolas; Henry Christopher;
2018 International Meeting of the European Calcium Society Poster Gating and permeation properties of two ORAI1 channel mutants associated with tubular aggregate myopathy. 09.09.2018 Hamburg, Germany Demaurex Nicolas; Bulla Monica; Hediger Matthias A.; Rajesh Bhardwaj;
2018 Fall Meeting of the Swiss Chemical Society Poster Synthesis of functionalized probes based on GSK7975A to study SOCE 07.09.2018 Lausanne, Switzerland Lochner Martin; Rajesh Bhardwaj; Hediger Matthias A.;
2018 Fall Meeting of the Swiss Chemical Society Poster Study of 2-aminoethoxydiphenyl borate (2-APB) analogues in MDA-MB-231 and MCF-7 cells towards Orai isoform-specific modulation of store-operated calcium entry (SOCE) 07.09.2018 Lausanne, Switzerland Lochner Martin; Schild Achille; Hediger Matthias A.; Rajesh Bhardwaj;
2018 15th International Symposium on Dendritic Cells Poster Unraveling the mechanism behind the regulation of cross-presentation by the SNARE Sec22b 10.06.2018 Aachen, Germany Demaurex Nicolas;
2018 FASEB SRC Conference “Calcium and Cell Function: From Mechanisms to Disease” Poster Two mutations associated with tubular aggregate myopathy differentially affect ORAI1 channel gating and selectivity 10.06.2018 Tahoe City, CA, USA, United States of America Demaurex Nicolas; Rajesh Bhardwaj; Hediger Matthias A.; Bulla Monica;
2018 FASEB SRC Conference “Calcium and Cell Function: From Mechanisms to Disease” Poster Ca2+ fluxes at endoplasmic reticulum - plasma membrane contact sites 10.06.2018 Tahoe City, CA, USA, United States of America Demaurex Nicolas; Henry Christopher;
2018 Signaling at Membrane Contact Sites Conference Talk given at a conference Calcium Signaling at Membrane Contact Sites during Phagocytosis 28.04.2018 Weill Cornell Medicine-Qatar, Doha, Qatar, Qatar Demaurex Nicolas;
2018 Seminar of the Department of Physiology, Anatomy, and Genetics, Oxford University Individual talk Role of STIM1 in phagocytic white blood cells 23.03.2018 Oxford, Great Britain and Northern Ireland Demaurex Nicolas;
2018, LS2 meeting Poster Gating and permeation properties of two ORAI1 channel mutants associated with tubular aggregate myopathy 12.02.2018 Lausanne, Switzerland, Switzerland Hediger Matthias A.; Bulla Monica; Demaurex Nicolas;
2018 LS2 meeting Poster Unravelling the role of the SNARE protein Sec22b in ER-phagosome membrane contact sites. 12.02.2018 Lausanne, Switzerland, Switzerland Demaurex Nicolas;
2018 LS2 meeting Poster Effects of 2-APB and GSK derivatives in innate immune cell lines 12.02.2018 Lausanne, Switzerland, Switzerland Demaurex Nicolas; Saul Stephanie;
Research seminar, Yonsei University College of Medicine Talk given at a conference Role of STIM1 in phagocytic white blood cells 13.09.2017 Wonju, Korean Republic (South Korea) Demaurex Nicolas;
Young Investigator Award Competition for young physiologists Poster Does the architecture of the endoplasmic reticulum alter the propagation of cytosolic Ca2+ signals and the efficiency of Ca2+ store refilling during store-operated calcium entry? 05.09.2017 Bern, Switzerland Demaurex Nicolas; Henry Christopher;
Swiss Summer School 2017 – Trends in Organic Synthesis Talk given at a conference Synthesis of functionalized probes based on GSK7975A to study SOCE 27.08.2017 Villars sur Ollon, Switzerland Lochner Martin; Rajesh Bhardwaj; Hediger Matthias A.;
2017 Fall Meeting of the Swiss Chemical Society Poster Synthesis of novel probes based on GSK7975A to study SOCE 21.08.2017 Bern, Switzerland Rajesh Bhardwaj; Hediger Matthias A.; Lochner Martin;
2017 Fall Meeting of the Swiss Chemical Society, Poster Diaryl borinic acids modulate store-operated calcium entry (SOCE) 21.08.2017 Bern, Switzerland Schild Achille; Lochner Martin; Hediger Matthias A.; Rajesh Bhardwaj;
SLC Transporters and Ion Channels in Drug Discovery and Preclinical Development Poster Does the structure of the endoplasmic reticulum alter its Ca2+ homeostasis during store-operated calcium entry (SOCE)? 06.08.2017 Lausanne, Switzerland Demaurex Nicolas; Henry Christopher;
SLC Transporters and Ion Channels in Drug Discovery and Preclinical Development Poster Effects of 2-APB and GSK derivatives in innate immune cell lines 06.08.2017 Lausanne, Switzerland Demaurex Nicolas; Saul Stephanie;
SLC Transporters and Ion Channels in Drug Discovery and Preclinical Development Poster Selective effect of 2-APB analogues on Orai1 and Orai3-mediated Ca2+ influx 06.08.2017 Lausanne, Switzerland Lochner Martin; Schild Achille; Rajesh Bhardwaj; Hediger Matthias A.; Wenger Nicolas; Augustynek Bartlomiej Stanislaw;
SLC Transporters and Ion Channels in Drug Discovery and Preclinical Development Poster Does calmodulin binding to ER Ca2+ sensors STIM1 or STIM2 fine-tunes store-operated Ca2+ entry? 06.08.2017 Lausanne, Switzerland Hediger Matthias A.; Rajesh Bhardwaj; Augustynek Bartlomiej Stanislaw; Henry Christopher; Demaurex Nicolas; Clemencon Benjamin;
Intracellular Calcium Signals: Generation, Function and Therapeutic Intervention Poster Selective effect of 2-APB analogues on Orai1 and Orai3-mediated Ca2+ influx 18.06.2017 Il Ciocco, Italy Lochner Martin; Schild Achille; Hediger Matthias A.; Rajesh Bhardwaj; Wenger Nicolas;
2017 Calcium signaling Gordon Research Seminar and Conference Poster ORAI1 Mutations with Distinct Channel Gating Defects Cause Tubular Aggregate Myopathy 17.06.2017 Il Ciocco, Italy Demaurex Nicolas;
Calcium signaling Gordon Research Seminar and Conference Talk given at a conference ORAI1 Mutations with Distinct Channel Gating Defects Cause Tubular Aggregate Myopathy 17.06.2017 Il Ciocco, Italy Demaurex Nicolas;
2017 Gordon Research Conference on Calcium Signaling Talk given at a conference Calcium signaling and neutrophil functions 17.06.2017 Il Ciocco, Italy Demaurex Nicolas;
2017 COST Meeting: Ion channels in immune disease Talk given at a conference STIM1 promotes phagosomal maturation and antigen cross- presentation in dendritic cells 23.03.2017 Belgrade, Serbien Demaurex Nicolas; Guido Daniele;
12th International Calreticulin workshop Talk given at a conference Calcium Signalling at Endoplasmic Reticulum Contact Sites 19.03.2017 Delphi, Greece Demaurex Nicolas;
61st Annual Meeting of the Biophysical Society Poster ORAI1 mutations with distinct channel gating defects linked to tubular aggregate myopathy 11.02.2017 New Orleans, United States of America Demaurex Nicolas; Hediger Matthias A.;
2017 Life Sciences Switzerland Tomorrow’s PI Competition Talk given at a conference Networking within the cell: Membrane contact sites as hubs for intracellular signaling in phagocytic immune cells 03.02.2017 Zürich, Switzerland Demaurex Nicolas;
2017 Life Sciences Switzerland Poster STIM1-mediated calcium signalling promotes phagosomal maturation and antigen cross- presentation in dendritic cells 03.02.2017 Zürich, Switzerland Guido Daniele; Demaurex Nicolas;
2016 Innate Immunity: The first line of defense (Online conference) Talk given at a conference Investigating the role of STIM1-mediated calcium signalling and ER-membrane contact sites in dendritic cell biology 15.11.2016 Euroscicon, Great Britain and Northern Ireland Demaurex Nicolas;
2016 Fall Meeting of the Swiss Chemical Society Poster “Design, synthesis and pharmacological characterisation of novel store-operated calcium channel (SOCE) modulators” 15.09.2016 Zürich, Switzerland Wenger Nicolas; Hediger Matthias A.; Lochner Martin; Schild Achille;
EMBO Workshop on organelle contact sites Talk given at a conference Calcium signaling at membrane contact sites during phagocytosis 15.09.2016 Domus de Maria, Italy Demaurex Nicolas;
Swiss Physiology Annual Meeting 2016 Talk given at a conference ORAI1 mutatioins with distinct channel gating defects cause tubular aggregate myopathy 06.09.2016 Fribourg, Switzerland Demaurex Nicolas;
FASEB SRC 2016 Calcium & Cell Function Poster Characterisation of new 2-APB analogues for their specificity on Orai channels 12.06.2016 Lisbon, Portugal Rajesh Bhardwaj; Wenger Nicolas; Hediger Matthias A.; Lochner Martin;
FASEB SRC 2016 Calcium & Cell Function Poster STIM1-mediated calcium signalling promotes phagosomal maturation and antigen cross- presentation in dendritic cells. 12.06.2016 Lisbon, Portugal Guido Daniele; Demaurex Nicolas;
FASEB SRC 2016 Calcium & Cell Function Poster ORAI1 mutations cause abnormal channel gating in tubular aggregate myopathy 12.06.2016 Lisbon, Portugal Demaurex Nicolas;
FASEB SRC 2016 Calcium & Cell Function Poster STIM1 ablation does not alter store-operated Ca2+ entry and effector functions in mouse neutrophils 12.06.2016 Lisbon, Portugal Saul Stephanie; Demaurex Nicolas;
FASEB SRC 2016 Calcium & Cell Function Talk given at a conference STIM1-mediated calcium signalling during phagocyosis 12.06.2016 Lisbon, Portugal Demaurex Nicolas;
50th annual scientific meeting of the European Society for Clinical Investigation Talk given at a conference STIM1 promotes antigen cross-presentation in dendritic cells by sustaining Ca2+-dependent phago-lysosome fusion 27.04.2016 Paris, France Guido Daniele; Demaurex Nicolas;
2016 Advances & Breakthroughs in Calcium Signaling Poster Characterisation of new 2-APB analogues for their specificity on Orai channels 07.04.2016 ​HONOLULU, HAWAII, United States of America Rajesh Bhardwaj; Lochner Martin; Hediger Matthias A.; Wenger Nicolas;
2016 annual meeting Life Sciences Switzerland Poster STIM1-mediated calcium signalling promotes phagosomal maturation and antigen cross- presentation in dendritic cells. 15.02.2016 Lausanne, Switzerland Guido Daniele; Demaurex Nicolas;
2016 annual meeting Life Sciences Switzerland Poster Orai1 Mutations associated with Tubular Aggregate Myopathy 15.02.2016 Lausanne, Switzerland Demaurex Nicolas;
2015 DC Ontogeny Functional Specialization and Targeting Talk given at a conference STIM1-mediated calcium signalling promotes phagosomal maturation and antigen cross- presentation in dendritic cells. 07.12.2015 Paris, France Demaurex Nicolas; Guido Daniele;
Organelle Crosstalk in Membrane Dynamics and Cell Signalling Poster STIM1-mediated calcium signalling promotes phagosomal maturation and antigen cross- presentation in dendritic cells. 26.10.2015 Edinburgh, Great Britain and Northern Ireland Demaurex Nicolas; Guido Daniele;
2015 Organelle Crosstalk in Membrane Dynamics and Cell Signalling Poster Endoplasmic reticulum-plasma membrane coupling by STIM2 and its regulation by Ca2+/Calmodulin 26.10.2015 Edinburgh, Great Britain and Northern Ireland Clemencon Benjamin; Hediger Matthias A.; Rajesh Bhardwaj; Demaurex Nicolas;


Self-organised

Title Date Place
IBMM Mini-Symposium: Transporters and Channels Part I 03.05.2017 Bern, Switzerland

Communication with the public

Communication Title Media Place Year
Talks/events/exhibitions Gymnasium Biel, 6.4.17 visit to DCB and IBMM Presentations&Lab Experiments Western Switzerland German-speaking Switzerland 2017
Talks/events/exhibitions Nacht der Forschung 16.09.2017, Universität Bern International 2017

Awards

Title Year
Audience Prize 2017 delivered to Nunes-Hasler Paula Life Sciences Switzerland Tomorrow’s PI Competition (selected as one of 6 from 72 applicants) 2017
First GRS poster prize to Bulla Monica at the “Calcium signaling” Gordon Research Seminar and Conference (June 17-23, 2017), Il Ciocco, Lucca (IT). 2017
Poster Prize by Oetliker foundation at 2017 Young Investigator Award Competition for young physiologists, Bern Poster Prize 600 CHF plus 1400 CHF as travel grant 2017
Travel grant delivered to Bulla Monica by the LS2 Physiology section for participation at the “Calcium signaling” Gordon Research Seminar and Conference (June 17-23, 2017), Il Ciocco, Lucca (IT) 2017

Associated projects

Number Title Start Funding scheme
125762 NCCR TransCure: From transport physiology to identification of therapeutic targets (phase I) 01.11.2010 National Centres of Competence in Research (NCCRs)
189042 Calcium signaling at membrane contact sites during phagocytosis 01.10.2019 Project funding (Div. I-III)
180326 The role of mitochondrial carriers in metabolic tuning and reprogramming by calcium flow across membrane contact sites 01.09.2018 Sinergia
169491 Calcium signaling at membrane contact sites during phagocytosis 01.10.2016 Project funding (Div. I-III)
149566 Signaling at membrane contact sites between the endoplasmic reticulum, mitochondria, and phagosomes 01.10.2013 Project funding (Div. I-III)

Abstract

Store-operated calcium entry (SOCE) is activated in response to depletion of the endoplasmic reticulum Ca2+ stores following stimulation of plasma membrane receptors. Key components of SOCE are the multiple isoforms of the ER-resident calcium sensors STIM1 and STIM2 and the Orai calcium channels (Orai1-3). However, the involvement of a myriad of other sensors and channels including TRP channels, Ca2+/calmodulin and SARAF also play a critical role in the regulation and function of SOCE. Investigations into the physiological significance of SOCE is an emerging field of great clinical interest, highly relevant to the immune system, cancer development and skeletal muscle defects. Membrane channels involved in SOCE can be powerful molecular targets through their ability to rapidly modulate important properties within the cell. However, pharmacological targeting of SOCE is currently limited to a few weak modulators lacking specificity. Using a synergistic approach across three disciplines (Molecular Biology, Physiology and Chemistry), we were now able to advance our understanding of the complexity of SOCE signaling. Through this Sinergia-funded project, we synthesized and identified isoform-specific modulators for the Orai1 and Orai3 channels that are helpful in our understanding of the functioning of these channels. We also identified new Orai-targeting drugs with anti-proliferation activity on breast cancer cells. Orai channels need to be opened from within the cell by activated STIM proteins. Mutations within the channels have been reported to open the channels without the requirement of STIM, or without the activation of STIM, and have been linked to the muscle disorder “Tubular aggregate myopathy” (TAM). We could explain how natural changes in single amino acids in patients suffering from this disease alter the properties of the channel. This progress clarifies our understanding of the disease mechanism. We also characterized the action of the commercially available inhibitor GSK7975A on several open channel mutants associated with TAM and highlighted its clinical relevance as the drug that could potently block different mutant channels. We also highlighted the role of STIM1 and its novel interaction partner UNC93B1 in an important aspect of innate immunity against intracellular pathogens, viruses and cancer cells.Based on our collaborative work, we are now also beginning to understand how binding of Ca2+/calmodulin to STIM1 inactivates the Orai1 channel. We found that H2O2 modifies STIM2 proteins and thereby inhibits their role in opening Orai channels. We identified important amino acids in STIM2 that are responsible for this action. We also studied different engineered mutations within different Orai channel isoforms and our date indicate that these channels exhibit different opening mechanisms.Our scientific achievements are demonstrated by five peer-reviewed international scientific publications, four review papers and another four scientific articles that are being written up. The success of our Sinergia network greatly benefited through very effective and fruitful interdisciplinary collaborations. We expect that the results from this project will facilitate the future development of more targeted drug treatment strategies for human diseases related to the immune system, muscle function and cancer development.
-