TRPM2:: a calcium influx pathway regulated by oxidative stress and the novel second messenger ADP-ribose

A unique functional property within the transient receptor potential (TRP) family of cation channels is the gating of TRP ( melastatin) 2 (TRPM2) channels by ADP-ribose (ADPR). ADPR binds to the intracellular C-terminal tail of TRPM2, a domain that shows homology to enzymes with pyrophosphatase activity. Cytosolic Ca2+ enhances TRPM2 gating by ADPR; ADPR and Ca2+ in concert may be an important messenger system mediating Ca2+ influx. Other stimuli of TRPM2 include NAD and H2O2 and cyclic ADPR, which may act synergistically with ADPR. H2O2, an experimental paradigm of oxidative stress, may also induce the formation of ADPR in the nucleus or mitochondria. In this review, we summarize the gating properties of TRPM2 and the proposed pathways of channel activation in vivo. TRPM2 is likely to be a key player in several signalling pathways, mediating cell death in response to oxidative stress or in reperfusion injury. Moreover, it plays a decisive role in experimentally induced diabetes mellitus and in the activation of leukocytes.