Cyclic ADP-ribose and hydrogen peroxide synergize with ADP-ribose in the activation of TRPM2 channels

被引：268

作者：

Kolisek, M ^{[1
]}

Beck, A ^{[1
]}

Fleig, A ^{[1
]}

Penner, R ^{[1
]}

机构：

[1] Univ Hawaii, John A Burns Sch Med, Queens Med Ctr, Lab Cell & Mol Signaling,Ctr Biomes Res, Honolulu, HI 96813 USA

来源：

MOLECULAR CELL | 2005年 / 18卷 / 01期

关键词：

D O I：

10.1016/j.molcel.2005.02.033

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：61 / 69

页数：9

共 30 条

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