Cooperative interaction of trp melastatin channel transient receptor potential (TRPM2) with its splice variant TRPM2 short variant is essential for Endothelial cell Apoptosis

Claudie M. Hecquet, Min Zhang, Manish Mittal, Stephen M. Vogel, Anke Di, Xiaopei Gao, Marcelo G. Bonini, Asrar B. Malik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

59 Scopus citations


RATIONALE:: 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 Ca permeable channel implicated in mediating apoptosis; however, the mechanisms of gating of the supranormal Ca 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 Ca 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 suppress TRPM2-dependent Ca 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 Ca 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 Ca 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 Ca and activation of the apoptosis program. Strategies aimed at preventing the uncoupling of TRPM2-S from TRPM2 and subsequent Ca gating during oxidative stress may mitigate endothelial apoptosis and its consequences in mediating vascular injury and inflammation.

Original languageEnglish (US)
Pages (from-to)469-479
Number of pages11
JournalCirculation research
Issue number3
StatePublished - Jan 31 2014
Externally publishedYes


  • apoptosis
  • capillary permeability
  • endothelium
  • inflammation

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology


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