3 years ago

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

2′-Deoxyadenosine 5′-diphosphoribose is an endogenous TRPM2 superagonist
Marianne Flato, Monika D Rozewitz, Adriana-Michelle Wolf Pérez, Andreas Bauche, Ralf Fliegert, Mareike Janus, Joanna M Watt, Barry V L Potter, Christelle Moreau, Angelika Harneit, Annette Rosche, Valerie Wolters, Feng Gu, Andreas H Guse, Tanja Kirchberger, Riekje Winzer
Transient receptor potential melastatin 2 (TRPM2) is a ligand-gated Ca2+-permeable nonselective cation channel. Whereas physiological stimuli, such as chemotactic agents, evoke controlled Ca2+ signals via TRPM2, pathophysiological stimuli such as reactive oxygen species and genotoxic stress result in prolonged TRPM2-mediated Ca2+ entry and, consequently, apoptosis. To date, adenosine 5′-diphosphoribose (ADPR) has been assumed to be the main agonist for TRPM2. Here we show that 2′-deoxy-ADPR was a significantly better TRPM2 agonist, inducing 10.4-fold higher whole-cell currents at saturation. Mechanistically, this increased activity was caused by a decreased rate of inactivation and higher average open probability. Using high-performance liquid chromatography (HPLC) and mass spectrometry, we detected endogenous 2′-deoxy-ADPR in Jurkat T lymphocytes. Consistently, cytosolic nicotinamide mononucleotide adenylyltransferase 2 (NMNAT-2) and nicotinamide adenine dinucleotide (NAD)-glycohydrolase CD38 sequentially catalyzed the synthesis of 2′-deoxy-ADPR from nicotinamide mononucleotide (NMN) and 2′-deoxy-ATP in vitro. Thus, 2′-deoxy-ADPR is an endogenous TRPM2 superagonist that may act as a cell signaling molecule.

Publisher URL: http://dx.doi.org/10.1038/nchembio.2415

DOI: 10.1038/nchembio.2415

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