2ʹ-Deoxyadenosine 5ʹ-diphosphoribose is an endogenous TRPM2 superagonist

Ralf Fliegert, Andreas Bauche, Adriana-Michelle Wolf Pérez, Joanna M Watt, Monika D. Rozewitz, Riekje Winzer, Mareike Janus, Feng Gu, Annette Rosche, Angelika Harneit, Marianne Flato, Christelle Moreau, Tanja Kirchberger, Valerie Wolters, Barry V. L. Potter, Andreas H Guse

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Transient receptor potential melastatin 2 (TRPM2), is a ligand-gated Ca2+-permeable non selective cation channel. While physiological stimuli, e.g. chemotactic agents, evoke controlled Ca2+ signals via TRPM2, pathophysiological signals, such as reactive oxygen species or genotoxic stress result in prolonged TRPM2-mediated Ca2+ entry and consequently apoptosis. To date, adenosine 5ʹ-diphosphoribose (ADPR, 1) has been assumed to be the main agonist for TRPM2. Here, we show that 2ʹ-deoxy-ADPR 2 was a significantly better TRPM2 agonist, inducing 10.4-fold 24 higher whole cell currents at saturation. Mechanistically, this increased activity was caused by decreased rate of inactivation and higher average open probability. Using high performance liquid chromatography (HPLC) and mass spectrometry, endogenous 2ʹ-deoxy-ADPR was detected in Jurkat T-lymphocytes. Consistently, cytosolic nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) and nicotinamide adenine dinucleotide (NAD)-glycohydrolase CD38 sequentially catalyzed synthesis of 2ʹ-deoxy-ADPR from nicotinamide mononucleotide and 2ʹ-deoxy-ATP in vitro. Thus, 2ʹ-deoxy-ADPR
31 is an endogenous TRPM2 superagonist that may act as cell signaling molecule.
LanguageEnglish
Pages1036-1044
Number of pages9
JournalNature Chemical Biology
Volume13
Early online date26 Jun 2017
DOIs
StatusPublished - 26 Jun 2017

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Nicotinamide-Nucleotide Adenylyltransferase
Nicotinamide Mononucleotide
Adenosine Diphosphate Ribose
Glycoside Hydrolases
NAD
DNA Damage
Cations
Reactive Oxygen Species
Mass Spectrometry
High Pressure Liquid Chromatography
Apoptosis
Ligands
T-Lymphocytes
2'-deoxyadenosine
In Vitro Techniques
2'-deoxyadenosine triphosphate

Cite this

Fliegert, R., Bauche, A., Wolf Pérez, A-M., Watt, J. M., Rozewitz, M. D., Winzer, R., ... Guse, A. H. (2017). 2ʹ-Deoxyadenosine 5ʹ-diphosphoribose is an endogenous TRPM2 superagonist. Nature Chemical Biology, 13, 1036-1044. https://doi.org/10.1038/nchembio.2415

2ʹ-Deoxyadenosine 5ʹ-diphosphoribose is an endogenous TRPM2 superagonist. / Fliegert, Ralf; Bauche, Andreas; Wolf Pérez, Adriana-Michelle ; Watt, Joanna M; Rozewitz, Monika D.; Winzer, Riekje; Janus, Mareike ; Gu, Feng ; Rosche, Annette ; Harneit, Angelika; Flato, Marianne; Moreau, Christelle; Kirchberger, Tanja; Wolters, Valerie; Potter, Barry V. L.; Guse, Andreas H.

In: Nature Chemical Biology, Vol. 13, 26.06.2017, p. 1036-1044.

Research output: Contribution to journalArticle

Fliegert, R, Bauche, A, Wolf Pérez, A-M, 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, '2ʹ-Deoxyadenosine 5ʹ-diphosphoribose is an endogenous TRPM2 superagonist', Nature Chemical Biology, vol. 13, pp. 1036-1044. https://doi.org/10.1038/nchembio.2415
Fliegert R, Bauche A, Wolf Pérez A-M, Watt JM, Rozewitz MD, Winzer R et al. 2ʹ-Deoxyadenosine 5ʹ-diphosphoribose is an endogenous TRPM2 superagonist. Nature Chemical Biology. 2017 Jun 26;13:1036-1044. https://doi.org/10.1038/nchembio.2415
Fliegert, Ralf ; Bauche, Andreas ; Wolf Pérez, Adriana-Michelle ; Watt, Joanna M ; Rozewitz, Monika D. ; Winzer, Riekje ; Janus, Mareike ; Gu, Feng ; Rosche, Annette ; Harneit, Angelika ; Flato, Marianne ; Moreau, Christelle ; Kirchberger, Tanja ; Wolters, Valerie ; Potter, Barry V. L. ; Guse, Andreas H. / 2ʹ-Deoxyadenosine 5ʹ-diphosphoribose is an endogenous TRPM2 superagonist. In: Nature Chemical Biology. 2017 ; Vol. 13. pp. 1036-1044.
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