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2′-Deoxyadenosine 5′-diphosphoribose is an endogenous TRPM2 superagonist
Nature Chemical Biology ( IF 14.8 ) Pub Date : 2017-06-26 00:00:00 , DOI: 10.1038/nchembio.2415
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

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.

中文翻译:

2'-脱氧腺苷5'-二磷酸核糖是内源性TRPM2超激动剂

瞬态受体电位褪黑素2(TRPM2)是配体门控的Ca 2+渗透性非选择性阳离子通道。生理刺激(例如趋化剂)通过TRPM2引起受控的Ca 2+信号,而病理生理刺激(例如活性氧和遗传毒性胁迫)则导致TRPM2介导的Ca 2+延长。进入,并因此导致细胞凋亡。迄今为止,腺苷5'-二磷酸核糖(ADPR)被认为是TRPM2的主要激动剂。在这里,我们显示2'-deoxy-ADPR是明显更好的TRPM2激动剂,在饱和时诱导高出全细胞电流10.4倍。从机械上讲,这种增加的活动是由于失活率降低和平均打开概率增加所致。使用高效液相色谱(HPLC)和质谱,我们在Jurkat T淋巴细胞中检测到了内源性2'-deoxy-ADPR。一致地,在体外,胞质烟酰胺单核苷酸腺苷酸转移酶2(NMNAT-2)和烟酰胺腺嘌呤二核苷酸(NAD)-糖水解酶CD38顺序地催化了烟酰胺单核苷酸(NMN)和2'-脱氧-ATP的合成2'-脱氧-ADPR 。因此,2'-脱氧-ADPR是可作为细胞信号分子的内源性TRPM2超激动剂。
更新日期:2017-08-19
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