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

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.