Skip to content


Open Access

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

  • Michaela Lichtenegger1,
  • Hannes Schleifer1,
  • Thomas Stockner2,
  • Christoph Romanin3,
  • Michael Poteser1 and
  • Klaus Groschner1Email author
BMC Pharmacology201010(Suppl 1):A15

Published: 16 November 2010


Pore StructureHEK293 CellSignaling FunctionCardiac RemodelIndirect Mechanism


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.

Authors’ Affiliations

Institute of Pharmaceutical Sciences – Pharmacology and Toxicology, University of Graz, Graz, Austria
Institute of Pharmacology, Center for Physiology and Pharmacology, Medical University of Vienna, Vienna, Austria
Institute of Biophysics, University of Linz, Linz, Austria


© Groschner et al; licensee BioMed Central Ltd. 2010

This article is published under license to BioMed Central Ltd.