Calcium Signalling Group

Mehrzellige Organismen benötigen Signalsysteme, um die Zusammenarbeit von Zellen mit unterschiedlicher Spezialisierung zu koordinieren. Nur eine solche koordinierte Interaktion bringt adäquate zelluläre Leistungen hervor. Dies führt in einem vielzelligen Organismus schließlich zu einem sinnvollen Zusammenwirken von Zellen, Organen und Organsystemen.
Die Calcium-Signalling Group im IBMZ untersucht solche Signalsysteme und erforscht dabei insbesondere die daran beteiligten Moleküle und deren Zusammenspiel bei der Erbringung adäquater zellulärer Leistungen.

1. Ryanodine receptors and NAADP in T cell biology

PI: Prof. Dr. Andreas H. Guse (in collaboration with Prof. Alexander Flügel, Universität Göttingen)

Team: Dr. Feng Gu, Dr. Viviana Granato, Dr. Sukanya Kannabiran, Dr. Anke Löhndorf, Macarena Hinrichs, MSc, Miriam Obel

Funding: DFG SFB1328, project A01(07/2018-06/2026)

In the 1st funding period of SFB1328 we identified novel components of NAADP signaling (DUOX2, HN1L/JPT2, RYR1). By combining our expertise regarding Ca2+ signaling and central nervous system (CNS) autoimmunity, currently we are (i) unraveling regulation of the NAADPH/NAADP redox cycle by DUOX enzymes and glucose 6-phosphate dehydrogenase (GLC6P-DH), (ii) probing CNS autoimmunity by knock-out of DUOX enzymes and availability of substrate O2, (iii) analyzing HN1L/JPT2’s binding sites for NAADP and for RYR1, (iv) constructing and validating a sensor for intracellular NAADP imaging, and (v) probing the role of NAADP signaling in T cell mediated autoimmunity in vivo.

MASTER-NAADP: a membrane permeable precursor of the Ca2+ mobilizing second messenger NAADP.
Krukenberg S*, Möckl F*, Weiß M, Dekiert P, Hofmann M, Gerlach F, Winterberg KJ, Kovacevic D, Khansahib I, Troost B, Hinrichs M, Granato V, Nawrocki M, Hub T, Tsvilovskyy V, Medert R, Woelk LM, Förster F, Li H, Werner R, Altfeld M, Huber S, Clarke OB, Freichel M, Diercks BP, Meier C*, Guse AH*.
Nat Commun. 2024 Sep 13;15(1):8008. doi: 10.1038/s41467-024-52024-y. PMID: 39271671; PMCID: PMC11399135. PubMed

Adhesion to laminin-1 and collagen IV induces the formation of Ca2+ microdomains that sensitize mouse T cells for activation.
Weiß M, Hernandez LC, Gil Montoya DC, Löhndorf A, Krüger A, Kopdag M, Uebler L, Landwehr M, Nawrocki M, Huber S, Woelk LM, Werner R, Failla AV, Flügel A, Dupont G, Guse AH, Diercks BP.
Science Signal . 2023 Jun 20;16(790):eabn9405.

2-Methoxyestradiol-3,17-O,O-bis-sulfamate inhibits store-operated Ca2+ entry in T lymphocytes and prevents experimental autoimmune encephalomyelitis.
Hosang L, Löhndorf A, Dohle W, Rosche A, Marry S, Diercks BP, Müller-Kirschbaum LC, Flügel LT, Potter BVL, Odoardi F, Guse AH, Flügel A.
Biochim Biophys Acta Mol Cell Res . 2023 Aug;1870(6):119485.

Three-Dimensional Model of Sub Plasmalemmal Ca2+ Microdomains Evoked by T Cell Receptor/CD3 Complex Stimulation.
Gil D, Diercks BP, Guse AH, Dupont G.
Front Mol Biosci . 2022 Feb 23;9:811145.

P2X4 and P2X7 are essential players in basal T cell activity and Ca2+ signaling milliseconds after T cell activation.
Brock VJ, Wolf IMA, Er-Lukowiak M, Lory N, Stähler T, Woelk LM, Mittrücker HW, Müller CE, Koch-Nolte F, Rissiek B, Werner R, Guse AH, Diercks BP.
Science Adv. 2022; 8(5):eabl9770.

Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation.
Gu F, Krüger A, Roggenkamp HG, Alpers R, Lodygin D, Jaquet V, Möckl F, Hernandez C LC, Winterberg K, Bauche A, Rosche A, Grasberger H, Kao JY, Schetelig D, Werner R, Schröder K, Carty M, Bowie AG, Huber S, Meier C, Mittrücker HW, Heeren J, Krause KH, Flügel A, Diercks B-P*, Guse AH*.
Science Signal . 2021; 14 eabe3800.

Stimulation of Local Cytosolic Calcium Release by Photothermal Heating for Studying Intra- and Intercellular Calcium Waves.
Zhu D, Feng L, Feliu N, Guse AH, Parak WJ.
Adv Mater 2021; 5:e2008261.

ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation.
Diercks BP, Werner R, Weidemüller P, Czarniak F, Hernandez L, Lehmann C, Rosche A, Krüger A, Kaufmann U, Vaeth M, Failla AV, Zobiak B, Kandil FI, Schetelig D, Ruthenbeck A, Meier C, Lodygin D, Flügel A, Ren D, Wolf IMA, Feske S, Guse AH (2018)
Science Signal 2018 Dec 18;11(561):eaat0358

Frontrunners of T cell activation: Initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor.
Wolf IM, Diercks BP, Gattkowski E, Czarniak F, Kempski J, Werner R, Schetelig D, Mittrücker HW, Schumacher V, von Osten M, Lodygin D, Flügel A, Fliegert R, Guse AH (2015)
Science Signal 8:ra102.

Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose.
Guse AH, da Silva CP, Berg I, Skapenko AL, Weber K, Heyer P, Hohenegger M, Ashamu GA, Schulze-Koops H, Potter BV, Mayr GW.
Nature 1999; 398:70-73.

2. Neuronal NAADP signalling during neuroinflammation

PI: Prof. Dr. Andreas H. Guse (in collaboration with Prof. Marc Freichel, Universität Heidelberg)

Team: Dr. Viviana Granato, Dr. Anke Löhndorf, NN, Miriam Obel

Funding: DFG FOR 7505 (01/25-12/28)

From our previous work, we hypothesize that under homeostatic conditions NAADP signalling is required for proper oscillatory Ca2+ signalling and survival (protective role of NAADP) during physiological glutamate stimulation at the post-synapse. In contrast, during inflammation-induced excitotoxic glutamate stimulation of extrasynaptic glutamate receptors, our results suggest that NAADP signalling contributes to the peak/plateau Ca2+ response, leading to neuronal Ca2+ overload and cell death (neurotoxic role of NAADP). We hypothesize that rebalancing Ca2+ signalling evoked by extrasynaptic glutamate signalling to physiological, oscillatory Ca2+ signalling, either by pharmacological or genetic intervention may constitute novel therapeutic avenues to protect from excitotoxicity during neuroinflammation.

MASTER-NAADP: a membrane permeable precursor of the Ca2+ mobilizing second messenger NAADP.
Krukenberg S*, Möckl F*, Weiß M, Dekiert P, Hofmann M, Gerlach F, Winterberg KJ, Kovacevic D, Khansahib I, Troost B, Hinrichs M, Granato V, Nawrocki M, Hub T, Tsvilovskyy V, Medert R, Woelk LM, Förster F, Li H, Werner R, Altfeld M, Huber S, Clarke OB, Freichel M, Diercks BP, Meier C*, Guse AH*.
Nat Commun. 2024 Sep 13;15(1):8008. doi: 10.1038/s41467-024-52024-y. PMID: 39271671; PMCID: PMC11399135. PubMed

Contribution of NAADP to Glutamate-Evoked Changes in Ca2+ Homeostasis in Mouse Hippocampal Neurons.
Hermann J, Bender M, Schumacher D, Woo MS, Shaposhnykov A, Rosenkranz SC, Kuryshev V, Meier C, Guse AH, Friese MA, Freichel M, Tsvilovskyy V.
Front Cell Dev Biol. 2020 Jun 25;8:496. doi: 10.3389/fcell.2020.00496. PMID: 32676502; PMCID: PMC7333232. PubMed

3. Dynamic architecture of Ca2+ microdomains in T cells: disentangling contribution of adenine nucleotides, Ca2+ release and Ca2+ entry.

PI: Priv.-Doz. Dr. Björn-Philipp Diercks (in collaboration with Prof. Rene Werner, UKE)

Team: Franziska Moeckl, MSc, Annette Rosche

Funding: DFG SFB1328, project A02(07/2018-06/2026)

Activation of T cells is closely related to the occurrence of Ca2+ microdomains. Our project aims to unravel the interplay of the complementary players during early T cell activation. Here, we focus on the formation of antigen-dependent Ca2+ micro- and even nanodomains, the characterization of ‘pure’ NAADP evoked Ca2+ signals as well as the visualization of the initial ATP concentration surrounding single T cells. To resolve and analyze associated Ca2+ micro-/nanodomains, the project develops and integrates innovative artificial intelligence and image processing algorithms and high-speed super-resolution live cell imaging.

MASTER-NAADP: a membrane permeable precursor of the Ca2+ mobilizing second messenger NAADP.
Krukenberg S*, Möckl F*, Weiß M, Dekiert P, Hofmann M, Gerlach F, Winterberg KJ, Kovacevic D, Khansahib I, Troost B, Hinrichs M, Granato V, Nawrocki M, Hub T, Tsvilovskyy V, Medert R, Woelk LM, Förster F, Li H, Werner R, Altfeld M, Huber S, Clarke OB, Freichel M, Diercks BP, Meier C*, Guse AH*.
Nat Commun. 2024 Sep 13;15(1):8008. doi: 10.1038/s41467-024-52024-y. PMID: 39271671; PMCID: PMC11399135. PubMed

Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation.
Brock VJ, Lory NC, Möckl F, Birus M, Stähler T, Woelk LM, Jaeckstein M, Heeren J, Koch-Nolte F, Rissiek B, Mittrücker HW, Guse AH, Werner R, Diercks BP.
Front Immunol. 2024 Feb 15;15:1258119. PubMed

Adhesion to laminin-1 and collagen IV induces the formation of Ca2+ microdomains that sensitize mouse T cells for activation.
Weiß M, Hernandez LC, Gil Montoya DC, Löhndorf A, Krüger A, Kopdag M, Uebler L, Landwehr M, Nawrocki M, Huber S, Woelk LM, Werner R, Failla AV, Flügel A, Dupont G, Guse AH, Diercks BP.
Sci Signal . 2023 Jun 20;16(790):eabn9405.

P2X4 and P2X7 are essential players in basal T cell activity and Ca2+ signaling milliseconds after T cell activation.
Brock VJ, Wolf IMA, Er-Lukowiak M, Lory N, Stähler T, Woelk LM, Mittrücker HW, Müller CE, Koch-Nolte F, Rissiek B, Werner R, Guse AH, Diercks BP.
Sci Adv. 2022 Feb 4;8(5):eabl9770.

Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation.
Gu F, Krüger A, Roggenkamp HG, Alpers R, Lodygin D, Jaquet V, Möckl F, Hernandez C LC, Winterberg K, Bauche A, Rosche A, Grasberger H, Kao JY, Schetelig D, Werner R, Schröder K, Carty M, Bowie AG, Huber S, Meier C, Mittrücker HW, Heeren J, Krause KH, Flügel A, Diercks B-P*, Guse AH*.
Science Signal. 2021; 14 eabe3800.

HN1L/JPT2: A signaling protein that connects NAADP generation to Ca2+ microdomain formation.
Roggenkamp HG, Khansahib I, Hernandez C LC, Zhang Y, Lodygin D, Krüger A, Gu F, Möckl F, Löhndorf A, Wolters V, Woike D, Rosche A, Bauche A, Schetelig D, Werner R, Schlüter H, Failla AV, Meier C, Fliegert R, Walseth TF, Flügel A, Diercks B-P*, Guse AH.
Science Signal . 2021; 14:eabd5647.

2-Methoxyestradiol and its derivatives inhibit store-operated Ca2+ entry in T cells: identification of a new and potent inhibitor.
Löhndorf A, Hosang L, Dohle W, Odoardi F, Waschkowski SA, Rosche A, Bauche A, Winzer R, Tolosa E, Windhorst S, Marry S, Flügel A, Potter BVL, Diercks B-P*, Guse AH*.
BBA Mol Cell Res . 2021; 118988.

High-Resolution Calcium Imaging Method for Local Calcium Signaling.
Diercks BP, Werner R, Schetelig D, Wolf IMA, Guse AH. (2019)
Methods Mol Biol. 1929:27-39.

ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation. Sci Signal 18;11(561).
Diercks BP, Werner R, Weidemüller P, Czarniak F, Hernandez L, Lehmann C, Rosche A, Krüger A, Kaufmann U, Vaeth M, Failla AV, Zobiak B, Kandil FI, Schetelig D, Ruthenbeck A, Meier C, Lodygin D, Flügel A, Ren D, Wolf IMA, Feske S, Guse AH. (2018)
Sci Signal 18;11(561).

Frontrunners of T cell activation: Initial, localized Ca2+ signals mediated by NAADP and the type 1 ryanodine receptor. Sci Signal 8: ra102.
Wolf IMA*, Diercks BP*, Gattkowski E, Czarniak F, Kempski J, Werner R, Schetelig D, Mittrücker HW, Schumacher V, von Osten M, Lodygin D, Flügel A, Fliegert R, Guse AH. (2015)
Sci Signal 8: ra102.

4. Impact of calcium and adenine nucleotide signaling on education and functionality of NK cells

PI: Priv.-Doz. Dr. Björn-Philipp Diercks (in collaboration with Prof. Marcus Altfeld, UKE)

Team: Fynn Gerlach, MSc, Annette Rosche

Funding: DFG, project 516286863, since 2023

Human natural killer (NK) cells play a central role in the innate immune defence. In a developmental process defined as NK-cell education, NK cells develop their tolerance towards self and gain their functional capacity to respond to altered self or foreign cells. However, the molecular mechanisms and pathways of NK cell education are not well understood. In our published and preliminary data, we already show that educated NK cells have stronger functional and metabolic activities, and exhibit higher Ca2+ responses. Furthermore, uneducated NK cells showed higher expression of the ATP gated cation channels P2X4 and P2X7 as well as the ectonucleotidase CD39. The role of intracellular adenine nucleotides, like nicotinic acid adenine dinucleotide phosphate (NAADP) and 3’,5’-cyclic AMP (cAMP) have not been studied in primary educated vs uneducated NK cells. Here, our preliminary data suggests that NAADP is not only important for short-term effector function but also downstream cytokine expression in NK cells and that an increase in cytosolic cAMP almost completely blocks NK cytotoxicity. In this project, we propose to disentangle the interplay between Ca2+- and adenine nucleotide signaling in human NK cell education and function. Understanding the molecular mechanisms and pathways underlying NK cell education will identify novel targets for immunotherapeutic interventions aimed at harnessing NK cells against tumors and viral infections.

MASTER-NAADP: a membrane permeable precursor of the Ca2+ mobilizing second messenger NAADP.
Krukenberg S*, Möckl F*, Weiß M, Dekiert P, Hofmann M, Gerlach F, Winterberg KJ, Kovacevic D, Khansahib I, Troost B, Hinrichs M, Granato V, Nawrocki M, Hub T, Tsvilovskyy V, Medert R, Woelk LM, Förster F, Li H, Werner R, Altfeld M, Huber S, Clarke OB, Freichel M, Diercks BP, Meier C*, Guse AH*.
Nat Commun. 2024 Sep 13;15(1):8008. doi: 10.1038/s41467-024-52024-y. PMID: 39271671; PMCID: PMC11399135. PubMed

Time-resolved role of P2X4 and P2X7 during CD8+ T cell activation.
Brock VJ, Lory NC, Möckl F, Birus M, Stähler T, Woelk LM, Jaeckstein M, Heeren J, Koch-Nolte F, Rissiek B, Mittrücker HW, Guse AH, Werner R, Diercks BP.
Front Immunol. 2024 Feb 15;15:1258119.

P2X4 and P2X7 are essential players in basal T cell activity and Ca2+ signaling milliseconds after T cell activation.
Brock VJ, Wolf IMA, Er-Lukowiak M, Lory N, Stähler T, Woelk LM, Mittrücker HW, Müller CE, Koch-Nolte F, Rissiek B, Werner R, Guse AH, Diercks B-P.
Sci Adv 2022, Vol. 8, Issue 5, eabl9770

Time Dependent Image Restoration of Low-SNR Live-Cell Ca2+ Fluorescence Microscopy Data.
Woelk LM, Kannabiran SA, Brock VJ, Gee CE, Lohr C, Guse AH, Diercks B-P, Werner R.
Int. Int. J. Mol. Sci..2021; 22, 11792. PubMed

High Metabolic Function and Resilience of NKG2A-Educated NK Cells.
Highton AJ, Diercks BP, Möckl F, Martrus G, Sauter J, Schmidt AH, Bunders MJ, Körner C, Guse AH, Altfeld M.
Front Immunol. 2020 Sep 30;11:559576 PubMed

High-Resolution Calcium Imaging Method for Local Calcium Signaling.
Diercks B-P, Werner R, Schetelig D, Wolf IMA, Guse AH.
Methods Mol Biol . 2019; 1929:27-39

5. Functional and structural analysis of the nucleotide-activated ion channel TRPM2.

PI: Dr. Ralf Fliegert (in collaboration with Dr. Maria Garcia Alai, EMBL Outstation Hamburg)

Team: Tessa Schwarzer, MSc, Steffi Etzold, Frederike Kulow

Funding: DFG SFB1328, project A05(07/2018-06/2026)

TRPM2 is a non-selective, Ca2+-permeable ion channel expressed in immune cells that can be activated by ADPR and 2dADPR. Within this project we will analyse the role of two distinct nucleotide binding domains for channel activation and their interplay with a recently identified Zn2+ binding site, and solve the structure of TRPM2 in its native lipid environment and in complex with PI(4,5)P2 and calmodulin to improve our understanding of the pleiotropic regulation of the channel. In addition we will investigate the spatio-temporal organization of the ADPR/2dADPR signalling pathway during chemotaxis of neutrophil granulocytes.

2'-deoxy-ADPR activates human TRPM2 faster than ADPR and thereby induces higher currents at physiological Ca2+ concentrations.
Pick J, Sander S, Etzold S, Rosche A, Tidow H, Guse AH, Fliegert R (2024)
Front Immunol 15:1294357

The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+ -binding domain essential for structural integrity and channel activity.
Sander S, Pick J, Gattkowski E, Fliegert R, Tidow H (2022)
Protein Sci 31(6):e4320

cADPR Does Not Activate TRPM2.
Riekehr WM, Sander S, Pick J, Tidow H, Bauche A, Guse AH, Fliegert R (2022)
Int J Mol Sci 23(6):3163

Does Cyclic ADP-Ribose (cADPR) Activate the Non-selective Cation Channel TRPM2?
Fliegert R, Riekehr WM, Guse AH (2020)
Front Immunol 11:2018

Synthesis of Terminal Ribose Analogues of Adenosine 5'-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
Baszczyňski O, Watt JM, Rozewitz MD, Guse AH, Fliegert R, Potter BVL (2019)
J Org Chem 84:6143-6157

Adenine nucleotides as paracrine mediators and intracellular second messengers in immunity and inflammation.
Fliegert R*, Heeren J*, Koch-Nolte F*, Nikolaev VO*, Lohr C*, Meier C*, Guse AH* (2019)
Biochem Soc Trans 47(1):329-337.

Novel CaM-binding motif in its NudT9H domain contributes to temperature sensitivity of TRPM2.
Gattkowski E, Johnsen A, Bauche A, Möckl F, Kulow F, Garcia Alai M, Rutherford TJ, Fliegert R*, Tidow H* (2019)
Biochim Biophys Acta Mol Cell Res 66(7):1162-1170.

2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist.
Fliegert R, Bauche A, Wolf Pérez AM, Watt JM, Rozewitz MD, Winzer R, Janus M, Gu F, Rosche A, Harneit A, Flato M, Moreau C, Kirchberger T, Wolters V, Potter BVL, Guse AH (2017)
Nat Chem Biol 13:10361044.

Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349.
Fliegert R, Watt JM, Schöbel A, Rozewitz MD, Moreau C, Kirchberger T, Thomas MP, Sick W, Araujo AC, Harneit A, Potter BVL, Guse AH (2017)
Biochem J 474:2159-2175.

NAADP signaling revisited.
Guse AH, Ernst IM, Fliegert R (2013)
Curr Top Med Chem 13:29782990.

6. Targeting the ADPR-binding macro domain associated de MARylation/dePARylation enzyme activity as novel approach towards SARS-CoV-2.

PI: Dr. Ralf Fliegert (in collaboration with Dr. Susanne Pfefferle, UKE, and Prof. Chris Meier, Organic Chemistry, University of Hamburg)

Team: Tessa Schwarzer, MSc, Steffi Etzold, Frederike Kulow

Funding: DFG SFB1328, project A18 (07/2018-06/2026)

As part of non-structural protein 3 (nsp3) SARS-CoV-2 harbours an ADPR-binding macrodomain with deADP-ribosylating activity that contributes to the suppression of the antiviral interferon response of the host. Aim of the project is to develop a structure-activity relationship for the viral macrodomain using ADPR analogues and to identify non-nucleotide inhibitors using a virtual screening approach. In addition we will analyse the role of the macrodomain in infection experiments using a reverse genetics approach and determine the effect of naturally occurring mutations in the macrodomain of nsp3 on enzymatic activity and viral replication.

2'-deoxy-ADPR activates human TRPM2 faster than ADPR and thereby induces higher currents at physiological Ca2+ concentrations.
Pick J, Sander S, Etzold S, Rosche A, Tidow H, Guse AH, Fliegert R (2024)
Front Immunol 15:1294357

The crystal structure of TRPM2 MHR1/2 domain reveals a conserved Zn2+ -binding domain essential for structural integrity and channel activity.
Sander S, Pick J, Gattkowski E, Fliegert R, Tidow H (2022)
Protein Sci 31(6):e4320

cADPR Does Not Activate TRPM2.
Riekehr WM, Sander S, Pick J, Tidow H, Bauche A, Guse AH, Fliegert R (2022)
Int J Mol Sci 23(6):3163

Does Cyclic ADP-Ribose (cADPR) Activate the Non-selective Cation Channel TRPM2?Fliegert R, Riekehr WM, Guse AH (2020)
Front Immunol 11:2018

Synthesis of Terminal Ribose Analogues of Adenosine 5'-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2
Baszczyňski O, Watt JM, Rozewitz MD, Guse AH, Fliegert R, Potter BVL (2019)
J Org Chem 84:6143-6157

Adenine nucleotides as paracrine mediators and intracellular second messengers in immunity and inflammation.
Fliegert R*, Heeren J*, Koch-Nolte F*, Nikolaev VO*, Lohr C*, Meier C*, Guse AH* (2019)
Biochem Soc Trans 47(1):329-337.

Novel CaM-binding motif in its NudT9H domain contributes to temperature sensitivity of TRPM2.
Gattkowski E, Johnsen A, Bauche A, Möckl F, Kulow F, Garcia Alai M, Rutherford TJ, Fliegert R*, Tidow H* (2019)
Biochim Biophys Acta Mol Cell Res 66(7):1162-1170.

2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist.
Fliegert R, Bauche A, Wolf Pérez AM, Watt JM, Rozewitz MD, Winzer R, Janus M, Gu F, Rosche A, Harneit A, Flato M, Moreau C, Kirchberger T, Wolters V, Potter BVL, Guse AH (2017)
Nat Chem Biol 13:10361044.

Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349.
Fliegert R, Watt JM, Schöbel A, Rozewitz MD, Moreau C, Kirchberger T, Thomas MP, Sick W, Araujo AC, Harneit A, Potter BVL, Guse AH (2017)
Biochem J 474:2159-2175.

NAADP signaling revisited.
Guse AH, Ernst IM, Fliegert R (2013)
Curr Top Med Chem 13:29782990.

• DFG SFB 1328 Adenine Nucleotidesin Immunity and Inflammation, projects A01, A02, A05, A18 (since 07/2018)
• DFG FOR 5705 NeuroFlame – Defence and demise of inflamed neurons (starting 01/2025)

• Fritz Nolte, Hamburg, Germany
• Eva Tolosa, Hamburg, Germany
• Rene Werner, Hamburg, Germany
• Samuel Huber, Hamburg, Germany
• Hans-Willi Mittrücker, Hamburg, Germany
• Nicola Gagliani, Hamburg, Germany
• Chris Meier, Hamburg, Germany
• Slava Nikolaev, Hamburg, Germany
• Wolfgang Parak, Hamburg, Germany
• Alexander Flügel, Göttingen, Germany
• Katrin Schröder, Frankfurt, Germany
• Marc Freichel, Heidelberg, Germany
• Genevieve Dupont, Brussels, Belgium
• Barry V.L. Potter, Oxford, United Kingdom
• Santina Bruzzone, Genova, Italy
• Andrew G. Bowie, Dublin, Ireland
• Helmut Grasberger, Ann Arbor, USA
• Karl-Heinz Krause, Geneva, Switzerland
• Timothy F. Walseth, Minneapolis, USA
• Oliver Clarke, New York, USA

MASTER-NAADP: a membrane permeable precursor of the Ca2+ mobilizing second messenger NAADP.
Krukenberg S*, Möckl F*, Weiß M, Dekiert P, Hofmann M, Gerlach F, Winterberg KJ, Kovacevic D, Khansahib I, Troost B, Hinrichs M, Granato V, Nawrocki M, Hub T, Tsvilovskyy V, Medert R, Woelk LM, Förster F, Li H, Werner R, Altfeld M, Huber S, Clarke OB, Freichel M, Diercks BP, Meier C*, Guse AH*.
Nat Commun. 2024 Sep 13;15(1):8008. doi: 10.1038/s41467-024-52024-y. PMID: 39271671; PMCID: PMC11399135

Dual NADPH oxidases DUOX1 and DUOX2 synthesize NAADP and are necessary for Ca2+ signaling during T cell activation.
Gu F, Krüger A, Roggenkamp HG, Alpers R, Lodygin D, Jaquet V, Möckl F, Hernandez C LC, Winterberg K, Bauche A, Rosche A, Grasberger H, Kao JY, Schetelig D, Werner R, Schröder K, Carty M, Bowie AG, Huber S, Meier C, Mittrücker HW, Heeren J, Krause KH, Flügel A, Diercks B-P*, Guse AH*.
Science Signal. 2021; 14 eabe3800.

HN1L/JPT2: A signaling protein that connects NAADP generation to Ca2+ microdomain formation.
Roggenkamp HG, Khansahib I, Hernandez C LC, Zhang Y, Lodygin D, Krüger A, Gu F, Möckl F, Löhndorf A, Wolters V, Woike D, Rosche A, Bauche A, Schetelig D, Werner R, Schlüter H, Failla AV, Meier C, Fliegert R, Walseth TF, Flügel A, Diercks B-P*, Guse AH*.
Science Signal. 2021; 14:eabd5647.

ORAI1, STIM1/2, and RYR1 shape subsecond Ca2+ microdomains upon T cell activation.
Diercks BP, Werner R, Weidemüller P, Czarniak F, Hernandez L, Lehmann C, Rosche A, Krüger A, Kaufmann U, Vaeth M, Failla AV, Zobiak B, Kandil FI, Schetelig D, Ruthenbeck A, Meier C, Lodygin D, Flügel A, Ren D, Wolf IMA, Feske S, Guse AH (2018)
Science Signal 2018 Dec 18;11(561):eaat0358