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. Tsvilovskyy V, Ottenheijm R, Kriebs U, Schütz A, Diakopoulos KA, 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 preventing uncontrolled Ca²⁺-release, exocytosis, and pancreatic tissue damage. Journal of Clinical Investigation, accepted Jan 2024.
2. 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.
3. 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.
4. Rosenkranz SC, Shaposhnykov AA, Träger S, Engler JB, Witte ME, Roth V, Vieira V, Paauw N, Bauer S, Schwencke-Westphal C, Schubert C, Bal LC, Schattling B, Pless O, van Horssen J, Freichel M, Friese MA. Enhancing mitochondrial activity in neurons protects against neurodegeneration in a mouse model of multiple sclerosis. Elife. 10: e61798, 2021
5. 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.
6. 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.
7. 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.
8. Bröker-Lai J, Kollewe A, Schindeldecker B, Pohle J, Nguyen C, Mathar I, Guzman R, Schwarz Y, Lai A, Weißgerber P, Schwegler H, Dietrich A, Both M, Sprengel R, Draguhn A, Köhr G, Fakler B, Flockerzi V, Bruns D, Freichel M: Heteromeric channels formed by TRPC1, TRPC4 and TRPC5 define hippocampal synaptic transmission and working memory. EMBO J 2017, 36: 2770-2789
9. Rixecker T, Mathar I, Medert R, Mannebach S, Pfeifer A, Lipp P, Tsvilovskyy V, Freichel M. TRPM4-mediated control of FcεRI-evoked Ca²⁺ elevation comprises enhanced plasmalemmal trafficking of TRPM4 channels in connective tissue type mast cells. Sci Rep 2016; 6: 32981.
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. Yuan Y, Arige V, Saito R, Mu Q, Bolsover SR, Keller M, Bracher F, Grimm C, Marchant JS, Yule DI, Patel S (2023) Two-pore channel-2 and inositol trisphosphate receptors coordinate Ca2+ signals between lysosomes and the endoplasmic reticulum. Cell Rep. accepted in press
2. 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.
3. 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.
4. 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. 
5. 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.
6. 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.
7. 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.
8. 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.
9. 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
10. Grimm C, Cuajungco MP, van Aken AFJ, Schnee M, Jörs S, Kros CJ, Ricci AJ, Heller S: A helix-breaking mutation in TRPML3 leads to constitutive activity underlying deafness in the varitint-waddler mouse. PNAS 2007; 104:19583-19588.

 

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