Molecular engineering of the TRPC3 pore structure identifies Ca2+ permeation through TRPC3 channels as a key determinant of cardiac calcineurin/NFAT signaling

Results Elimination of Ca 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 Ca that was independent of voltagegated CaV1.2 channels. By contrast, a Ca 2+ impermeant TRPC3 mutant strongly promoted endothelin-induced Ca signals in HL1 cells via enhanced activity of CaV1.2 channels without concomitant NFAT translocation. Conclusions Our results demonstrate two strictly separated Ca signaling functions of cardiac TRPC3 channels as well as a tight and efficient link between TRPC3-mediated Ca permeation and calcineurin/NFAT signaling.