Nuclear Ca2+ regulates cardiomyocyte function.
In the heart, cytosolic Ca(2+) signals are well-characterized events that participate in the activation of cell contraction. In contrast, nuclear Ca(2+) contribution to cardiomyocyte function remains elusive. Here, we examined functional consequences of buffering nuclear Ca(2+) in neonatal cardiomyocytes. We report that cardiomyocytes contain a nucleoplasmic reticulum, which expresses both ryanodine receptor (RyR) and inositol 1,4,5-trisphosphate receptor (InsP(3)R), providing a possible way for active regulation of nuclear Ca(2+). Adenovirus constructs encoding the Ca(2+) buffer protein parvalbumin were targeted to the nucleus with a nuclear localization signal (Ad-PV-NLS) or to the cytoplasm with a nuclear exclusion signal (Ad-PV-NES). A decrease in the amplitude of global Ca(2+) transients and RyR-II expression, as well as an increase in cell beating rate were observed in Ad-PV-NES and Ad-PV-NLS cells. When nuclear Ca(2+) buffering was imposed nuclear enlargement, increased calcineurin expression, NFAT translocation to the nucleus and subcellular redistribution of atrial natriuretic peptide were observed. Furthermore, prolongation of action potential duration occurred in adult ventricular myocytes. These results suggest that nuclear Ca(2+) levels underlie the regulation of specific protein targets and thereby modulate cardiomyocyte function. The local nuclear Ca(2+) signaling and the structures that control it constitute a novel regulatory motif in the heart.
Guatimosim
Silvia
S
Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte CEP: 31270-901, Brazil.
Amaya
Maria Jimena
MJ
Guerra
Mateus T
MT
Aguiar
Carla J
CJ
Goes
Alfredo M
AM
Gómez-Viquez
Norma Leticia
NL
Rodrigues
Michele A
MA
Gomes
Dawidson A
DA
Martins-Cruz
Juliana
J
Lederer
W J
WJ
Leite
M Fatima
MF
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D005453:Fluorescence; D005455:Fluorescent Antibody Technique; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism*; D009685:Nuclear Envelope / Q000378:metabolism*; D019913:Nuclear Localization Signals; D010320:Parvalbumins / Q000235:genetics / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism*
D053496:Inositol 1,4,5-Trisphosphate Receptors; D019913:Nuclear Localization Signals; D010320:Parvalbumins; D019837:Ryanodine Receptor Calcium Release Channel; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium