Cooperative Interaction of trp Melastatin Channel TRPM2 with its Splice Variant TRPM2-S is Essential for Endothelial Cell Apoptosis
2013
Rationale: Oxidants generated by activated endothelial cells are known to induce apoptosis, a pathogenic feature of vascular injury and inflammation from multiple etiologies. The melastatin-family transient receptor potential 2 (TRPM2) channel is an oxidant-sensitive Ca 2+ permeable channel implicated in mediating apoptosis; however, the mechanisms of gating of the supra-normal Ca 2+ influx required for initiating of apoptosis are not understood. Objective: Here we addressed the role TRPM2 and its interaction with the short splice variant TRPM2-S in mediating the Ca 2+ entry burst required for induction of endothelial cell apoptosis. Methods and Results: We observed that TRPM2-S was basally associated with TRPM2 in the endothelial plasmalemma and this interaction functioned to constitutively suppress TRPM2-dependent Ca 2+ gating. ROS production in endothelial cells or directly applying ROS induced PKCα activation and phosphorylation of TRPM2 at Ser 39. This in turn stimulated a large entry of Ca 2+ and activated the apoptosis pathway. A similar TRPM2-dependent endothelial apoptosis mechanism was seen in intact vessels. The PKCα-activated phospho-switch opened the TRPM2 channel to allow large Ca 2+ influx by releasing TRPM2-S inhibition of TRPM2, which in turn activated caspase-3 and cleaved the caspase substrate poly(ADP-ribose) polymerase. Conclusions: Here we describs a fundamental mechanism by which activation of the trp super-family TRPM2 channel induces apoptosis of endothelial cells. The signaling mechanism involves ROS-induced PKCα activation resulting in phosphorylation of TRPM2-S that allows enhanced TRPM2-mediated gating of Ca 2+ and activation of the apoptosis program. Strategies aimed at preventing the uncoupling of TRPM2-S from TRPM2 and subsequent Ca 2+ gating during oxidative stress may mitigate endothelial apoptosis and its consequences in mediating vascular injury and inflammation.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
3
References
2
Citations
NaN
KQI