Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels
Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels
复制标题
DOI：
10.1016/j.molcel.2005.02.033
复制
发表时间：
2005-04-01
期刊：
影响因子：
16
通讯作者：
Penner, R
中科院分区：
文献类型：
--
作者：
Kolisek, M;Beck, A;Penner, R
Melastatin相关的瞬时受体电位通道TRPM 2是一种质膜Ca 2+渗透性阳离子通道，通过细胞内腺苷二磷酸核糖（ADPR）与通道的酶促NuD结构域结合而激活。通道活性也见于烟酰胺二核苷酸（NAD（+））和过氧化氢（H2 O2），但其作用机制尚不清楚。在这里，我们确定环腺苷二磷酸核糖（cADPR）作为TRPM 2的激动剂具有双重活性：在100 μ M以上的浓度，cADPR可以门控通道本身，而10 μ M的较低浓度具有增强作用，使ADPR门控通道在纳摩尔浓度。ADPR的分解产物一磷酸腺苷（AMP）特异性抑制ADPR，但不抑制cADPR介导的TRPM 2门控，而cADPR拮抗剂8-Br-cADPR则表现出反向阻断特异性。我们的研究结果建立TRPM 2作为一个符合检测器ADPR和cADPR信号，并提供了一个功能的背景下，cADPR作为第二信使的Ca 2+内流。
The melastatin-related transient receptor potential channel TRPM2 is a plasma membrane Ca2+ -permeable cation channel that is activated by intracellular adenosine diphosphoribose (ADPR) binding to the channel's enzymatic Nudix domain. Channel activity is also seen with nicotinamide dinucleotide (NAD(+)) and hydrogen peroxide (H2O2), but their mechanisms of action remain unknown. Here, we identify cyclic adenosine diphosphoribose (cADPR) as an agonist of TRPM2 with dual activity: at concentrations above 100 mu M, cADPR can gate the channel by itself, whereas lower concentrations of 10 mu M have a potentiating effect that enables ADPR to gate the channel at nano-molar concentrations. ADPR's breakdown product adenosine monophosphate (AMP) specifically inhibits ADPR, but not cADPR-mediated gating of TRPM2, whereas the cADPR antagonist 8-Br-cADPR exhibits the reverse block specificity. Our results establish TRPM2 as a coincidence detector for ADPR and cADPR signaling and provide a functional context for cADPR as a second messenger for Ca2+ influx.