title: Cooperative interaction of trp melastatin channel transient receptor potential (TRPM2) with its splice variant TRPM2 short variant is essential for endothelial cell apoptosis.
abstract: BACKGROUND
  Oxidants generated by activated endothelial cells are known to induce apoptosis, a pathogenic feature of vascular injury and inflammation from multiple pathogeneses. The melastatin-family transient receptor potential 2 (TRPM2) channel is an oxidant-sensitive Ca2+ permeable channel implicated in mediating apoptosis; however, the mechanisms of gating of the supranormal Ca2+ influx required for initiating of apoptosis are not understood.
  
  
  OBJECTIVE
  Here, we addressed the role of TRPM2 and its interaction with the short splice variant TRPM2 short variant (TRPM2-S) in mediating the Ca2+ entry burst required for induction of endothelial cell apoptosis.
  
  
  RESULTS
  We observed that TRPM2-S was basally associated with TRPM2 in the endothelial plasmalemma, and this interaction functioned to suppress TRPM2-dependent Ca2+ gating constitutively. Reactive oxygen species production in endothelial cells or directly applying reactive oxygen species induced protein kinase C-α activation and phosphorylation of TRPM2 at Ser 39. This in turn stimulated a large entry of Ca2+ and activated the apoptosis pathway. A similar TRPM2-dependent endothelial apoptosis mechanism was seen in intact vessels. The protein kinase C-α-activated phosphoswitch opened the TRPM2 channel to allow large Ca2+ 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 describe a fundamental mechanism by which activation of the trp superfamily TRPM2 channel induces apoptosis of endothelial cells. The signaling mechanism involves reactive oxygen species-induced protein kinase C-α activation resulting in phosphorylation of TRPM2-S that allows enhanced TRPM2-mediated gating of Ca2+ and activation of the apoptosis program. Strategies aimed at preventing the uncoupling of TRPM2-S from TRPM2 and subsequent Ca2+ gating during oxidative stress may mitigate endothelial apoptosis and its consequences in mediating vascular injury and inflammation.
authors: From the Department of Pharmacology and the Center for Lung and Vascular Biology (C.M.H., M.Z., M.M., S.M.V., A.D., X.G., M.G.B., A.B.M.) and Section of Cardiology (M.G.B.), College of Medicine, University of Illinois, Chicago.
authors: Claudie M
authors: CM
authors: Hecquet
authors: Min
authors: M
authors: Zhang
authors: Manish
authors: M
authors: Mittal
authors: Stephen M
authors: SM
authors: Vogel
authors: Anke
authors: A
authors: Di
authors: Xiaopei
authors: X
authors: Gao
authors: Marcelo G
authors: MG
authors: Bonini
authors: Asrar B
authors: AB
authors: Malik
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics*; D020013:Calcium Signaling / Q000235:genetics; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism*; D014644:Genetic Variation; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D005810:Multigene Family; D011485:Protein Binding / Q000235:genetics; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D012326:RNA Splicing / Q000235:genetics*; D050053:TRPM Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D050053:TRPM Cation Channels; C121934:TRPM2 protein, human
keywords: apoptosis; capillary permeability; endothelium; inflammation