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 4

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HDAC5 nuclear export is Ca2+ dependent but not activated by global Ca2+ ...
HDAC5 nuclear export is Ca2+ dependent but not activated by global Ca2+ transients. (A) Adenoviral HDAC5-GFP–infected myocytes were also loaded with Rhod-2 to measure [Ca2+]i. Rhod-2 is more concentrated in the nucleus (nuc), complicating Ca2+ transient calibration there. (B) HDAC5 remained nuclear when myocytes were field stimulated at 0.5 Hz (n = 5) or 1 Hz (n = 7) for 60 minutes or even at 2 Hz (not shown). (C) In permeabilized myocytes, internal [Ca2+] was increased from 100 nM to 500 nM (at 60 minutes) (n = 7). 2,3 butanedione monoxime (5 mM) was used to prevent contraction. (D) Expected local [Ca2+] gradient around the mouth of an InsP3R Ca2+ channel: [Ca2+]i = [Ca2+]Init + q/(2πDr) × erfc{r/(2√Dr)}, where q = single channel current (0.1 pA), D = diffusion coefficient (600 μm2/s), [Ca2+]Init = 100 nM, erfc = complementary error function, and r = radial distance from the channel mouth for hemispheric diffusion. This is the steady state, achieved in approximately 10 μs without buffering and much less than 1 ms when local Ca2+ buffering is included (26).