Local InsP3-dependent perinuclear Ca2+ signaling in cardiac myocyte excitation-transcription coupling
Xu Wu, … , Joan Heller Brown, Donald M. Bers
Xu Wu, … , Joan Heller Brown, Donald M. Bers
Published March 1, 2006
Citation Information: J Clin Invest. 2006;116(3):675-682. https://doi.org/10.1172/JCI27374.
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Research Article Cardiology

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

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 (InsP3Rs) 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 InsP3R. 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.

Authors

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

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Figure 3

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ET-1–induced HDAC5 nuclear export is dependent on InsP3R and Ca2+ in Ins...
ET-1–induced HDAC5 nuclear export is dependent on InsP3R and Ca2+ in InsP3-sensitive stores. (A) HDAC5-GFP–expressing myocytes were pretreated with 2 μM 2-APB (n = 6) or 10 μM Bis I (n = 5) for 30 minutes, followed by application of 100 nM ET-1. (B) SR and nuclear envelope Ca2+ stores were depleted by preincubation with SR/ER Ca2+-ATPase (SERCA) inhibitor TG 1 μM (n = 7) for 10 minutes. Insets are the Fluo-5N images, showing that this TG treatment depleted nuclear envelope Ca2+ stores. (C) In permeabilized HDAC5-GFP expressing myocytes, 10 μM adenophostin was applied after 30 minutes at 100 nM [Ca2+]i (n = 8). HDAC5 nuclear export was measured as the decrease of nuclear fluorescence. In the permeabilized cell, cytosolic concentration is irrelevant as HDAC5-GFP can readily diffuse to the bath. (D) ET-1–induced HDAC5 nuclear export assessed in mouse ventricular myocytes that lack InsP3R2 (InsP3R 2 KO) or WT littermates. (E) Fluo-5N–loaded myocytes were permeabilized and treated without or with 10 μM adenophostin for 30 minutes. Nuclear envelope Ca2+ release was indicated by decreased Fluo-5N fluorescence.