A21

A21

Mast cells are immune cells that essentially contribute to various inflammatory processes. Ca²⁺ entry and cytosolic Ca²⁺ rise is essential for inflammatory mediator release from mast cells. Adenine nucleotides (AN) such as adenosine, ATP or NAADP regulate mast cell Ca²⁺ homeostasis and function via endolysosomal two-pore channels (TPCs) and plasmalemmal channels. We will apply (endolysosomal) patch-clamp electrophysiology, imaging techniques, cell biological assays and mouse models to investigate the role of Orai and TPC channels and novel interaction partners of these for mast cell-mediated inflammation.

Prof. Dr. Marc Freichel

Selected publications (*equal contribution)

 

1. Bröker-Lai J, Rego Terol J, Richter C, Mathar I, Wirth A, Kopf S, Moreno-Pérez A, Büttner M, Tan LL, Makke M, Poschet G, Hermann J, Tsvilovskyy V, Haberkorn U, Wartenberg P, Susperreguy S, Berlin M, Ottenheijm R, Philippaert K, Wu M, Wiedemann T, Herzig S, Belkacemi A, Levinson RT, Agarwal N, Camacho Londoño JE, Klebl B, Dinkel K, Zufall F, Nussbaumer P, Boehm U, Hell R, Nawroth P, Birnbaumer L, Leinders-Zufall T, Kuner R, Zorn M, Bruns D, Schwarz Y, Freichel M. TRPC5 controls the adrenaline-mediated counter regulation of hypoglycemia. EMBO J. 2024 Dec;43(23):5813-5836.
2. 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. MASTER-NAADP: a membrane permeable precursor of the Ca²⁺mobilizing second messenger NAADP. Nat Commun. 2024 Sep 13;15(1):8008.
3. Woo MS, Mayer C, Binkle-Ladisch L, Sonner JK, Rosenkranz SC, Shaposhnykov A, Rothammer N, Tsvilovskyy V, Lorenz SM, Raich L, Bal LC, Vieira V, Wagner I, Bauer S, Glatzel M, Conrad M, Merkler D, Freichel M, Friese MA. STING orchestrates the neuronal inflammatory stress response in multiple sclerosis. Cell. 2024 Jul 25;187(15):4043-4060.e30. 
4. Tsvilovskyy V, Ottenheijm R, Kriebs U, Schütz A, Diakopoulos KN, Jha A, Bildl W, Wirth A, Böck J, Jaślan D, Ferro I, Taberner FJ, Kalinina O, Hildebrand S, Wissenbach U, Weissgerber P, Vogt D, Eberhagen C, Mannebach S, Berlin M, Kuryshev V, Schumacher D, Philippaert K, Camacho-Londoño JE, Mathar I, Dieterich C, Klugbauer N, Biel M, Wahl-Schott C, Lipp P, Flockerzi V, Zischka H, Algül H, Lechner SG, Lesina M, Grimm C, Fakler B, Schulte U, Muallem S, Freichel M. OCaR1 endows exocytic vesicles with autoregulatory competence by preventing uncontrolled Ca²⁺ release, exocytosis, and pancreatic tissue damage. J Clin Invest. 2024 Apr 1;134(7):e169428.
5. Medert R, Thumberger T, Tavhelidse-Suck T, Hub T, Kellner T, Oguchi Y, Dlugosz S, Zimmermann F, Wittbrodt J, Freichel M. Efficient single copy integration via homology-directed repair (scHDR) by 5'modification of large DNA donor fragments in mice Nucleic Acids Res. 2023 Feb 22;51(3):e14.
6. Woo MS, Ufer F, Sonner JK, Belkacemi A, Tintelnot J, Sáez PJ, Krieg PF, Mayer C, Binkle-Ladisch L, Engler JB, Bauer S, Kursawe N, Vieira V, Mannebach S, Freichel M, Flockerzi V, Vargas P, Friese MA. Calcium channel β3 subunit regulates ATP-dependent migration of dendritic cells Sci Adv. 2023 Sep 22;9(38):eadh1653.
7. Arlt E, Fraticelli M, Tsvilovskyy V, Nadolni W, Breit A, O’Neill TJ, Resenberger S, Wennemuth G, Wahl-Schott C, Biel M, Grimm C, Freichel M, Gudermann T, Klugbauer N, Boekhoff I, Zierler S. TPC1 deficiency or blockade augments systemic anaphylaxis and mast cell activity. PNAS USA 2020; 13:201920122.
8. Tsvilovskyy V, Solis-Lopez A, Almering J, Richter C, Birnbaumer L, Dietrich A, Freichel M. Analysis of Mrgprb2 Receptor-Evoked Ca²⁺ Signaling in Bone Marrow Derived (BMMC) and Peritoneal (PMC) Mast Cells of TRPC-Deficient Mice. Front Immunol. 2020; 11: 564.
9. Tsvilovskyy V, Solís-López A, Schumacher D, Medert R, Roers A, Kriebs U, Freichel M. Deletion of Orai2 augments endogenous CRAC currents and degranulation in mast cells leading to enhanced anaphylaxis. Cell Calcium 2018; 71, 24-33.
10. Vennekens R, Olausson J, Meissner M, Bloch W, Mathar I, Philipp SE, Schmitz F, Weissgerber P, Nilius B, Flockerzi V, Freichel M: Increased IgE-dependent mast cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat Immunol 2007, 8, 312-20.

Prof. Dr. Christian Grimm

Selected publications

1. Abrahamian C, Tang R, Deutsch R, Ouologuem L, Weiden EM, Kudrina V, Blenninger J, Rilling J, Feldmann C, Kuss S, Stepanov Y, Rosato AS, Calvo GT, Soengas MS, Mayr D, Fröhlich T, Gudermann T, Biel M, Wahl-Schott C, Chen CC, Bartel K, Grimm C. Rab7a is an enhancer of TPC2 activity regulating melanoma progression through modulation of the GSK3β/β-Catenin/MITF-axis. Nat Commun. 2024 Nov 19;15(1):10008.
2. Yuan Y, Arige V, Saito R, Mu Q, Brailoiu GC, Pereira GJS, Bolsover SR, Keller M, Bracher F, Grimm C, Brailoiu E, Marchant JS, Yule DI, Patel S. Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca²⁺ signals between lysosomes and the endoplasmic reticulum. Cell Rep. 2024 Jan 23;43(1):113628.
3. Goretzko J, Pauels I, Heitzig N, Thomas K, Kardell M, Naß J, Krogsaeter EK, Schloer S, Spix B, Linard Matos AL, Leser C, Wegner T, Glorius F, Bracher F, Gerke V, Rossaint J, Grimm C, Rescher U. P-selectin-dependent leukocyte adhesion is governed by endolysosomal two-pore channel 2. Cell Rep. 2023 Nov 29;42(12):113501.
4. Saito R, Mu Q, Yuan Y, Rubio-Alarcón M, Eznarriaga M, Zhao P, Gunaratne G, Kumar S, Keller M, Bracher F, Grimm C, Brailoiu E, Marchant JS, Rahman T, Patel S. Convergent activation of Ca²⁺ permeability in two-pore channel 2 through distinct molecular routes. Sci Signal. 2023 Aug 22;16(799):eadg0661.
5. Xu M, Zhong XZ, Huang P, Jaślan D, Wang P, Sun X, Weiden EM, El Hiani Y, Grimm C*, Dong XP*. TRPML3/BK complex promotes autophagy and bacterial clearance by providing a positive feedback regulation of mTOR via PI3P. Proc Natl Acad Sci U S A. 2023 Aug 22;120(34):e2215777120. 
6. Chen C-C, Krogsaeter E, Butz E, Li Y, Puertollano R, Wahl-Schott C, Biel M, Grimm C: TRPML2 is an osmo-/mechano-sensitive cation channel in endolysosomal organelles. Science Adv 2020 6(46):eabb5064.
7. Chao Y-K, Schludi V, Chen C-C, Butz E, Nguyen P, Müller M, Krüger J, Kammerbauer C, Vollmar A, Berking C, Biel M, Wahl-Schott C, Grimm C: TPC2 polymorphisms associated with a human hair pigmentation phenotype result in gain of channel function by independent mechanisms. PNAS 2017 114:E8595-E8602.
8. Chen C-C, Chunlei C, Fenske S, Butz E, Chao Y-K, Biel M, Ren D, Wahl-Schott C, Grimm C: Patch clamp technique to characterize ion channels in individual intact endolysosomes. Nature Protoc 2017; 12:1639-1658.
9. Chen C-C, Keller M, Hess M, Schiffmann R, Urban N, Wolfgardt A, Schaefer M, Bracher F, Biel M, Wahl-Schott C, Grimm C: A small molecule restores function to TRPML1 mutant isoforms responsible for mucolipidosis type IV. Nature Commun 2014;5:4681.
10. Grimm, C, Holdt, LM, Chen, C-C, Hassan, S, Müller, C, Jörs, S, Cuny, H, Kissing, S, Schröder, B, Butz, E., Northoff, B., Castonguay, J., Luber, C.A., Moser, M., Spahn, S., Lüllmann-Rauch, R., Fendel, C, Klugbauer, N, Griesbeck, O, Haas, A, Mann, M, Bracher, F, Teupser, D, Saftig, P, Biel, M, Wahl-Schott, C: High susceptibility to fatty liver disease in two-pore channel 2-deficient mice. Nature Commun 5:4699, 2014

 

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