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PKCα‐dependent opening of the oxidant‐sensitive calcium channel TRPM2 induces apoptosis of lung endothelial cells
Author(s) -
Hecquet Claudie M,
Di Anke,
Gao Xiaopei,
Vogel Stephen M,
Malik Asrar B
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.670.3
Subject(s) - trpm2 , phosphorylation , chemistry , gating , protein kinase c , oxidative phosphorylation , cancer research , microbiology and biotechnology , transient receptor potential channel , apoptosis , biochemistry , biology , receptor , biophysics
We addressed the relationship between oxidant‐activated transient receptor potential melastatin 2 (TRPM2) channel and its associated short splice variant (TRPM2‐S), in the gating of Ca 2+ , and how it mediates apoptosis of lung endothelial cells (LECs). We show that PKCα‐induced phosphorylation of TRPM2‐S prevents its association with TRPM2, and thereby activates Ca 2+ gating activity. Results show that H 2 O 2 induces association of PKCα with TRPM2‐S and phosphorylation of TRPM2‐S, and promotes dissociation of TRPM2‐S from TRPM2. Inhibition of PKCα activity and mutation of PKCα phosphorylation site (S39A) on TRPM2‐S N‐terminus prevents the uncoupling of TRPM2‐S from TRPM2‐L. Dissociation of TRPM2‐S from TRPM2‐L induces opening of TRPM2 channel and enables Ca 2+ entry in LECs. This unique mechanism of TRPM2 channel activation was crucial for induction of oxidant mediated apoptosis of LECs. We conclude that oxidant‐induced LEC apoptosis is critically dependent of PKCα phosphorylation of TRPM2‐S and gating of Ca 2+ via TRPM2; thus, pharmacologically maintaining TRPM2‐S and TRPM2 interaction by inhibiting PKCα activation, may be a novel means of preventing oxidative lung injury. Supported by AHA Grant SDG (10SDG2610057).