Skeletal muscle dysfunction; Store-operated calcium entry; Immunology; SOCE; TRP channel; Calcium; Cancer; Calcium channel; Immune system
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
Demaurex Nicolas, Saul Stephanie (2018), The role of STIM proteins in neutrophil functions, in The Journal of Physiology
, 596(14), 2699-2708.
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.
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.
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.
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.
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.
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.
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.
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.
Bhardwaj Rajesh, Hediger Matthias A., Demaurex Nicolas (2016), Redox modulation of STIM-ORAI signaling, in Cell Calcium
, 60(2), 142-152.
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.
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.