Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling

Xu Wu, Tong Zhang, Julie Bossuyt, Xiaodong Li, Timothy A. McKinsey, John R. Dedman, Eric N. Olson, Ju Chen, Joan Heller Brown, Donald M. Bers

Research output: Contribution to journalArticle

369 Scopus citations

Abstract

Previous work showed that calmodulin (CaM) and Ca2+-CaM- dependent protein kinase II (CaMKII) are somehow involved in cardiac hypertrophic signaling, that inositol 1,4,5-trisphosphate receptors (InsP 3Rs) in ventricular myocytes are mainly in the nuclear envelope, where they associate with CaMKII, and that class II histone deacetylases (e.g., HDAC5) suppress hypertrophic gene transcription. Furthermore, HDAC phosphorylation in response to neurohumoral stimuli that induce hypertrophy, such as endothelin-1 (ET-1), activates HDAC nuclear export, thereby regulating cardiac myocyte transcription. Here we demonstrate a detailed mechanistic convergence of these 3 issues in adult ventricular myocytes. We show that ET-1, which activates plasmalemmal G protein-coupled receptors and InsP3 production, elicits local nuclear envelope Ca2+ release via InsP 3R. This local Ca2+ release activates nuclear CaMKII, which triggers HDAC5 phosphorylation and nuclear export (derepressing transcription). Remarkably, this Ca2+-dependent pathway cannot be activated by the global Ca2+ transients that cause contraction at each heartbeat. This novel local Ca2+ signaling in excitation-transcription coupling is analogous to but separate (and insulated) from that involved in excitation-contraction coupling. Thus, myocytes can distinguish simultaneous local and global Ca2+ signals involved in contractile activation from those targeting gene expression.

Original languageEnglish (US)
Pages (from-to)675-682
Number of pages8
JournalJournal of Clinical Investigation
Volume116
Issue number3
DOIs
StatePublished - Mar 1 2006

ASJC Scopus subject areas

  • Medicine(all)

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    Wu, X., Zhang, T., Bossuyt, J., Li, X., McKinsey, T. A., Dedman, J. R., Olson, E. N., Chen, J., Brown, J. H., & Bers, D. M. (2006). Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling. Journal of Clinical Investigation, 116(3), 675-682. https://doi.org/10.1172/JCI27374