title: Nuclear Ca2+ regulates cardiomyocyte function.
abstract: 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.
authors.affiliation: Department of Physiology and Biophysics, Federal University of Minas Gerais, Av. Antônio Carlos 6627, Belo Horizonte CEP: 31270-901, Brazil.
authors.forename: Silvia
authors.initials: S
authors.lastname: Guatimosim
authors.forename: Maria Jimena
authors.initials: MJ
authors.lastname: Amaya
authors.forename: Mateus T
authors.initials: MT
authors.lastname: Guerra
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Aguiar
authors.forename: Alfredo M
authors.initials: AM
authors.lastname: Goes
authors.forename: Norma Leticia
authors.initials: NL
authors.lastname: Gómez-Viquez
authors.forename: Michele A
authors.initials: MA
authors.lastname: Rodrigues
authors.forename: Dawidson A
authors.initials: DA
authors.lastname: Gomes
authors.forename: Juliana
authors.initials: J
authors.lastname: Martins-Cruz
authors.forename: W J
authors.initials: WJ
authors.lastname: Lederer
authors.forename: M Fatima
authors.initials: MF
authors.lastname: Leite
mesh_terms: 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*
chemical_list: 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