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. Fliegert R, Riekehr WM, Guse AH (2020) Does Cyclic ADP-Ribose (cADPR) Activate the Non-selective Cation Channel TRPM2?. Front Immunol 11:2018
2. Baszczyňski O, Watt JM, Rozewitz MD, Guse AH, Fliegert R, Potter BVL (2019) Synthesis of Terminal Ribose Analogues of Adenosine 5'-Diphosphate Ribose as Probes for the Transient Receptor Potential Cation Channel TRPM2. J Org Chem  84:6143-6157
3. Fliegert R*, Heeren J*, Koch-Nolte F*, Nikolaev VO*, Lohr C*, Meier C*, Guse AH* (2019) Adenine nucleotides as paracrine mediators and intracellular second messengers in immunity and inflammation. Biochem Soc Trans 47(1):329-337.
4. Gattkowski E, Johnsen A, Bauche A, Möckl F, Kulow F, Garcia Alai M, Rutherford TJ, Fliegert R*, Tidow H* (2019) Novel CaM-binding motif in its NudT9H domain contributes to temperature sensitivity of TRPM2. Biochim Biophys Acta Mol Cell Res 66(7):1162-1170.
5. 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) 2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist. Nat Chem Biol13:10361044.
6. 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) Ligand-induced activation of human TRPM2 requires the terminal ribose of ADPR and involves Arg1433 and Tyr1349. Biochem J474:2159-2175.
7. Guse AH, Ernst IM, Fliegert R (2013) NAADP signaling revisited. Curr Top Med Chem 13:29782990.
8. Schwarz N*, Fliegert R*, Adriouch S*, Seman M, Guse AH, Haag F, Koch-Nolte F (2009) Activation of the P2X7 ion channel by soluble and covalently bound ligands. Purinergic Signal 5:139-149.
9. Fliegert R, Gasser A, Guse AH (2007) Regulation of calcium signalling by adenine-based second messengers. Biochem Soc Trans 35:109-114.
10. Fliegert R, Glassmeier G, Schmid F, Cornils K, Genisyuerek S, Harneit A, Schwarz JR, Guse AH (2007) Modulation of Ca2+ entry and plasma membrane potential by human TRPM4b. FEBS J 274:704713.

Prof. Dr. Christian Grimm

Selected publications

 

1. 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 71, 24-33, 2018

2. Arlt, E., Fraticelli, M., Tsvilovskyy, V., Nadolni, W., Breit, A., O’Neill, T.J., 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, 13:201920122, 2020

3. 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 6(46):eabb5064, 2020.

4. 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

5. 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 ma st cell activation and anaphylactic responses in mice lacking the calcium-activated nonselective cation channel TRPM4. Nat Immunol 8: 312-20, 2007

6. Rixecker T, Mathar I, Medert R, Mannebach S, Pfeifer A, Lipp P, Tsvilovskyy V, Freichel M: TRPM4-mediated control of FcεRI-evoked Ca(2+) elevation comprises enhanced plasmalemmal trafficking of TRPM4 channels in connective tissue type mast cells. Sci Rep 6: 32981, 2016

7.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. 11: 564, 2020

8. Spix B, Butz ES, Chen CC, Rosato AS, Tang R, Jeridi A, Kudrina V, Plesch E, Wartenberg P, Arlt E, Briukhovetska D, Ansari M, Günsel GG, Conlon TM, Wyatt A, Wetzel S, Teupser D, Holdt LM, Ectors F, Boekhoff I, Boehm U, García-Añoveros J, Saftig P, Giera M, Kobold S, Schiller HB, Zierler S, Gudermann T, Wahl-Schott C, Bracher F, Yildirim AÖ, Biel M, Grimm C:Lung emphysema and impaired macrophage elastase clearance in mucolipin 3 deficient mice. Nature Commun 13(1):318, 2022

9. 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 12:1639-1658, 2017

10. R. Medert, T. Thumberger, T. Tavhelidse, T. Hub, T. Kellner, Y. Oguchi, S. Dlugosz, F. Zimmermann, J. Wittbrodt, M. Freichel, Efficient single copy integration via homology-directed repair (scHDR) by 5'modification of large DNA donor fragments in mice. Nucleic Acid Research, in press (2022).

Our Team