Medizinische Universität Graz - Research portal
Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Poteser, M; Schleifer, H; Lichtenegger, M; Schernthaner, M; Stockner, T; Kappe, CO; Glasnov, TN; Romanin, C; Groschner, K.
PKC-dependent coupling of calcium permeation through transient receptor potential canonical 3 (TRPC3) to calcineurin signaling in HL-1 myocytes.
Proc Natl Acad Sci U S A. 2011; 108(26):10556-10561
Doi: 10.1073/pnas.1106183108
[OPEN ACCESS]
Web of Science
PubMed
FullText
FullText_MUG
- Leading authors Med Uni Graz
- Groschner Klaus
- Poteser Michael
- Co-authors Med Uni Graz
- Lichtenegger Michaela
- Schernthaner Michaela
- Schleifer Hannes
- Altmetrics:
- Dimensions Citations:
- Plum Analytics:
- Scite (citation analytics):
- Abstract:
- Cardiac transient receptor potential canonical (TRPC) channels are crucial upstream components of Ca(2+)/calcineurin/nuclear factor of activated T cells (NFAT) signaling, thereby controlling cardiac transcriptional programs. The linkage between TRPC-mediated Ca(2+) signals and NFAT activity is still incompletely understood. TRPC conductances may govern calcineurin activity and NFAT translocation by supplying Ca(2+) either directly through the TRPC pore into a regulatory microdomain or indirectly via promotion of voltage-dependent Ca(2+) entry. Here, we show that a point mutation in the TRPC3 selectivity filter (E630Q), which disrupts Ca(2+) 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 (Ca(V)1.2) channel-mediated Ca(2+) entry in HL-1 cells, thereby generating a dihydropyridine-sensitive Ca(2+) 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 Ca(2+) signaling into a transcriptionally silent mode. Thus, we demonstrate a dichotomy of TRPC-mediated Ca(2+) signaling in the heart constituting two distinct pathways that are differentially linked to gene transcription. Coupling of TRPC3 activity to NFAT translocation requires microdomain Ca(2+) signaling by PKC-modified TRPC3 complexes. Our results identify TRPC3 as a pivotal signaling gateway in Ca(2+)-dependent control of cardiac gene expression.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Calcineurin - metabolism
- Calcium - metabolism
- Cell Line -
- Humans -
- Ion Transport -
- Mice -
- Myocardium - cytology Myocardium - enzymology Myocardium - metabolism
- NFATC Transcription Factors - metabolism
- Phosphorylation -
- Protein Kinase C - metabolism
- Signal Transduction -
- TRPC Cation Channels - metabolism
- Find related publications in this database (Keywords)
- Ca(2+) homeostasis
- NFATc1 transactivation
- transient receptor potential
- canonical
- divalent permeation