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Molecular engineering of the TRPC3 pore structure identifies Ca2+ permeation through TRPC3 channels as a key determinant of cardiac calcineurin/NFAT signaling
BMC Pharmacology volume 10, Article number: A15 (2010)
TRPC channels have been identified as key players in cardiac remodeling and as crucial upstream components of NFAT signaling. The linkage between non-selective TRPC conductances and calcineurin/NFAT signaling may involve either direct TRC-mediated Ca2+ entry or indirect mechanisms involving crosstalk with other cardiac Ca2+ transport systems.
The pore structure of TRPC3 was analyzed by site-directed mutagenesis guided by a molecular modeling approach combined with patch-clamp measurements in the HEK293 expression system. TRPC3-mediated Ca2+ entry as well as NFAT translocation was investigated by fluorescence microscopy using Fura-2 and expression of a GFP-NFAT fusion protein in HEK293 as well as in HL1 cells.
Elimination of Ca2+ permeation through TRPC3 abrogated its ability to trigger NFAT translocation in both HEK293 cells and in HL-1 atrial myocytes. Wild-type TRPC3 was found capable of initiating NFAT translocation in atrial myocytes by a small, homogenous elevation of cytoplasmic Ca2+ that was independent of voltage-gated CaV1.2 channels. By contrast, a Ca2+ impermeant TRPC3 mutant strongly promoted endothelin-induced Ca2+ signals in HL1 cells via enhanced activity of CaV1.2 channels without concomitant NFAT translocation.
Our results demonstrate two strictly separated Ca2+ signaling functions of cardiac TRPC3 channels as well as a tight and efficient link between TRPC3-mediated Ca2+ permeation and calcineurin/NFAT signaling.
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Lichtenegger, M., Schleifer, H., Stockner, T. et al. Molecular engineering of the TRPC3 pore structure identifies Ca2+ permeation through TRPC3 channels as a key determinant of cardiac calcineurin/NFAT signaling. BMC Pharmacol 10, A15 (2010). https://doi.org/10.1186/1471-2210-10-S1-A15
- Pore Structure
- HEK293 Cell
- Signaling Function
- Cardiac Remodel
- Indirect Mechanism