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First published online July 12, 2005
doi: 10.1242/10.1242/jcs.02446

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Nuclear inositol 1,4,5-trisphosphate receptors regulate local Ca²⁺ transients and modulate cAMP response element binding protein phosphorylation

¹ Centro de Estudios Moleculares de la Célula, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Independencia 1027, Santiago 7, Chile
² Institut Fédératif de Neurobiologie Alfred Fessard, Laboratoire de Neurobiologie Cellulaire et Moléculaire, UPR 9040 CNRS, 91198 Gif-sur-Yvette CEDEX, France
³ Laboratorio de Fisiología de La Conducta, Facultad de Medicina, Universidad de Los Andes, Mérida 5101, Venezuela
⁴ Department of Physiology, Stritch School of Medicine, Loyola University Chicago, Maywood, Illinois 60153, USA

^* Author for correspondence (e-mail: ejaimovi{at}med.uchile.cl)

Accepted 20 April 2005

Several lines of evidence indicate that increases in nuclear Ca²⁺ have specific biological effects that differ from those of cytosolic Ca²⁺, suggesting that they occur independently. The mechanisms involved in controlling nuclear Ca²⁺ signaling are both controversial and still poorly understood. Using hypotonic shock combined with mechanical disruption, we obtained and characterized a fraction of purified nuclei from cultured rat skeletal myotubes. Both immunoblot studies and radiolabeled inositol 1,4,5-trisphosphate [IP₃] binding revealed an important concentration of IP₃ receptors in the nuclear fraction. Immunofluorescence and immunoelectron microscopy studies localized type-1 and type-3 IP₃ receptors in the nucleus with type-1 receptors preferentially localized in the inner nuclear membrane. Type-2 IP₃ receptor was confined to the sarcoplasmic reticulum. Isolated nuclei responded to IP₃ with rapid and transient Ca²⁺ concentration elevations, which were inhibited by known blockers of IP₃ signals. Similar results were obtained with isolated nuclei from the 1B5 cell line, which does not express ryanodine receptors but releases nuclear Ca²⁺ in an IP₃-dependent manner. Nuclear Ca²⁺ increases triggered by IP₃ evoked phosphorylation of cAMP response element binding protein with kinetics compatible with sequential activation. These results support the idea that Ca²⁺ signals, mediated by nuclear IP₃ receptors in muscle cells, are part of a distinct Ca²⁺ release component that originates in the nucleus and probably participates in gene regulation mediated by cAMP response element binding protein.

Key words: Skeletal muscle, Myonuclei, Inositol 1, 4, 5-trisphosphate receptors, Nuclear envelope, Transcription factors, Gene expression

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