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PKCα REGULATION OF TRPM2 CHANNEL ACTIVATION OF Ca 2+ ENTRY IN ENDOTHELIAL CELLS
Author(s) -
Hecquet Claudie M,
Vogel Stephen M,
Malik Asrar B
Publication year - 2009
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.23.1_supplement.937.9
Subject(s) - trpm2 , transient receptor potential channel , protein kinase c , phosphorylation , gene silencing , chemistry , microbiology and biotechnology , peroxynitrite , biochemistry , receptor , biology , superoxide , gene , enzyme
Oxidant signaling, through the production of oxygen metabolites such as hydrogen peroxide (H 2 O 2 ), regulates multiple endothelial functions. We have previously shown that the transient receptor potential melastatin (TRPM) channel 2 (TRPM2) mediates H 2 O 2 ‐induced Ca 2+ entry and endothelial hyper‐permeability (Hecquet et al., Circ Res 2008; 102: 347‐355). Here, we provide evidence that PKCα regulates oxidant‐induced Ca 2+ entry by modulation of TRPM2 channel activity. H 2 O 2 ‐elicted Ca 2+ entry via TRPM2 channels was significantly reduced by PKCα‐silencing or inhibition, suggesting that PKCα positively regulates Ca 2+ entry through TRPM2. The H 2 O 2 ‐elicited decrease in transendothelial electrical resistance (TER) was also reduced by TRPM2‐silencing (by 39 ± 9 %), PKCα‐silencing (by 36 ± 6 %) and to a similar degree by PKCα‐ or TRPM2‐silencing (by 40 ± 8 %), signifying that PKCα plays a permissive role in the opening of TRPM2 channels. In addition, H 2 O 2 induced rapid PKCα co‐localization with TRPM2‐S (the dominant‐negative splice variant of TRPM2 that associates with TRPM2) and the phosphorylation of TRPM2‐S. Thus, PKCα phosphorylation of TRPM2‐S regulates the opening of TRPM2 channels enabling H 2 O 2 ‐induced Ca 2+ entry in endothelial cells.