2'-Deoxyadenosine 5'-diphosphoribose is an endogenous TRPM2 superagonist.
Ralf FliegertAndreas BaucheAdriana-Michelle Wolf PérezJoanna M WattMonika D RozewitzRiekje WinzerMareike JanusFeng GuAnnette RoscheAngelika HarneitMarianne FlatoChristelle MoreauTanja KirchbergerValerie WoltersBarry V L PotterAndreas H GusePublished in: Nature chemical biology (2017)
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.
Keyphrases
- high performance liquid chromatography
- mass spectrometry
- simultaneous determination
- single cell
- tandem mass spectrometry
- reactive oxygen species
- protein kinase
- solid phase extraction
- oxidative stress
- ms ms
- cell therapy
- cell death
- endoplasmic reticulum stress
- minimally invasive
- high resolution
- capillary electrophoresis
- heat stress
- binding protein