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Cardiac transient receptor potential canonical (TRPC) channels are crucial upstream components of Ca2+ /calcineurin/nuclear factor of activated T cells (NFAT) signaling, thereby controlling cardiac transcriptional programs. The linkage between TRPC-mediated Ca2+ signals and NFAT activity is still incompletely understood. TRPC conductances may govern calcineurin activity and NFAT translocation by supplying Ca2+ either directly through the TRPC pore into a regulatory microdomain or indirectly via promotion of voltage-dependent Ca2+ entry. Here, we show that a point mutation in the TRPC3 selectivity filter (E630Q), which disrupts Ca2+ permeability but preserves monovalent permeation, abrogates agonist-induced NFAT signaling in HEK293 cells as well as in murine HL-1 atrial myocytes. The E630Q mutation fully retains the ability to convert phospholipase C-linked stimuli into L-type (CaV 1.2) channel-mediated Ca2+ entry in HL-1 cells, thereby generating a dihydropyridine-sensitive Ca2+ signal that is isolated from the NFAT pathway. Prevention of PKC-dependent modulation of TRPC3 by either inhibition of cellular kinase activity or mutation of a critical phosphorylation site in TRPC3 (T573A), which disrupts targeting of calcineurin into the channel complex, converts cardiac TRPC3-mediated Ca2+ signaling into a transcriptionally silent mode. Thus, we demonstrate a dichotomy of TRPC-mediated Ca2+ signaling in the heart constituting two distinct pathways that are differentially linked to gene transcription. Coupling of TRPC3 activity to NFAT translocation requires microdomain Ca2+ signaling by PKC-modified TRPC3 complexes. Our results identify TRPC3 as a pivotal signaling gateway in Ca2+ -dependent control of cardiac gene expression.

PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes