摘要：The human non-selective cation channel TRPM2 represents a mediator of apoptosis triggered by oxidative stress. The principal agonist ADP-ribose binds to the cytosolic domain of TRPM2, which is homologous to the human ADP-ribose pyrophosphatase NUDT9. To further elucidate the structure-function relationship of this channel, we characterised a TRPM2 orthologue from the cnidarian Nematostella vectensis , after its expression in a human cell line. This far distant relative shows only 31% total sequence similarity to h TRPM2, while its C-terminal domain has a greater resemblance to the NUDT9 enzyme. Current through nv TRPM2 was induced by ADPR, with a more pronounced sensitivity and faster kinetics than in h TRPM2. In contrast to h TRPM2, there was no response to H2O2 and hardly any modulatory effect by intracellular Ca2+. The deletion of a stretch of 15 residues from the NUDT9 domain of nv TRPM2, which is absent in h TRPM2, did not change the response to ADPR but enabled activation of the channel by H2O2 and increased the effects of intracellular Ca2+. These findings shed new light on the evolution of TRPM2 and establish nv TRPM2 as a promising tool to decipher its complex gating mechanisms.
