Intracellular Ca2+ Oscillations, a Potential Pacemaking Mechanism in Early Embryonic Heart Cells

Sasse, Philipp; Zhang, Jianbao; Cleemann, Lars; Morad, Martin; Hescheler, Juergen; Fleischmann, Bernd K.

doi:10.1085/jgp.200609575

Cited by 82 publications

(112 citation statements)

References 47 publications

(66 reference statements)

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“…However, repetitive Ca 2+ signals and rhythmic contractions occur in these RyR-deficient animals at E7−9.5 [87,88]. In addition, the Ca 2+ signals in young embryonic heart cells are insensitive to experimental maneuvers that inhibit voltage-activated Ca 2+ channels or Na + /Ca 2+ exchange, but are affected by agents that deplete intracellular Ca 2+ stores [89] (but see [90] for an alternative view). Taken together, these data indicate that periodic Ca 2+ release from intracellular stores occurs in young embryonic heart cells, and that the channels involved are not RyRs.…”

Section: Ip 3 Signaling In Cardiac Developmentmentioning

confidence: 99%

See 1 more Smart Citation

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

169

149

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Inositol 1,4,5-trisphosphate (IP 3 ) is a ubiquitous intracellular messenger regulating diverse functions in almost all mammalian cell types. It is generated by membrane receptors that couple to phospholipase C (PLC), an enzyme which liberates IP 3 from phosphatidylinositol 4,5-bisphosphate (PIP 2 ). The major action of IP 3 , which is hydrophilic and thus translocates from the membrane into the cytoplasm, is to induce Ca 2+ release from endogenous stores through IP 3 receptors (IP 3 Rs). Cardiac excitation-contraction coupling relies largely on ryanodine receptor (RyR)-induced Ca 2+ release from the sarcoplasmic reticulum. Myocytes express a significantly larger number of RyRs compared to IP 3 Rs (∼100:1), and furthermore they experience substantial fluxes of Ca 2+ with each heartbeat. Therefore, the role of IP 3 and IP 3 -mediated Ca 2+ signaling in cardiac myocytes has long been enigmatic. Recent evidence, however, indicates that despite their paucity cardiac IP 3 Rs may play crucial roles in regulating diverse cardiac functions. Strategic localization of IP 3 Rs in cytoplasmic compartments and the nucleus enables them to participate in subsarcolemmal, bulk cytoplasmic and nuclear Ca 2+ signaling in embryonic stem cell-derived and neonatal cardiomyocytes, and in adult cardiac myocytes from the atria and ventricles. Intriguingly, expression of both IP 3 Rs and membrane receptors that couple to PLC/IP 3 signaling is altered in cardiac disease such as atrial fibrillation or heart failure, suggesting the involvement of IP 3 signaling in the pathology of these diseases. Thus, IP 3 exerts important physiological and pathological functions in the heart, ranging from the regulation of pacemaking, excitation-contraction and excitation-transcription coupling to the initiation and/or progression of arrhythmias, hypertrophy and heart failure. KeywordsInositol 1,4,5-trisphosphate; Cardiac myocyte; Calcium; Inotropy; Arrhythmias; Nucleus; Hypertrophy © 2008 Elsevier Inc. All rights reserved. * Corresponding author. E-mail address: jens.kockskaemper@meduni-graz.at (J. Kockskämper).. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript The discovery of IP 3A quarter of a century ago it was shown that D-myo inositol 1,4,5-trisphosphate (IP 3 ) releases Ca 2+ from a non-mitochondrial internal Ca 2+ store [1]. Since this hallmark discovery, IP 3 has emerged as a ubiquitous intracellular messenger, releasing Ca 2+ from stores through activation of IP 3 receptors (IP 3 Rs) in almost all eukaryotic cells. The major IP 3 -sensitive intracellular Ca 2+ store is the endoplasmic reticulum. However, IP 3 has also been shown to release Ca 2+ stored in other compartments, such as the Golgi and the nuclear envelope [2]. In addition, IP 3 Rs are present on the plasma membrane of some cell types, where they can gate Ca 2+ influx [3]. A crucial role for IP 3 -dependent Ca 2+ release has been demonstrated in many mammalian cell types, ranging from tiny platelets, where it initiates blood clottin...

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Section: Ip 3 Signaling In Cardiac Developmentmentioning

confidence: 99%

“…For example, the spontaneous Ca 2+ oscillations in murine embryonic cells were sensitive to application of 2-APB (an IP 3 R antagonist [42]) [89]. Furthermore, IP 3 Rs are expressed in the inner mass of embryos at E5.5, and are clearly evident within the developing heart tube at E8.5 [91].…”

Section: Ip 3 Signaling In Cardiac Developmentmentioning

confidence: 99%

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Kockskämper

Zima

Roderick

et al. 2008

Journal of Molecular and Cellular Cardiology

169

149

View full text Add to dashboard Cite

show abstract

“…Calcium release and cycling via the ryanodine receptor (RyR2), the sarcoplasmic reticulum calcium ATPase (SERCA2), the sodium calcium exchanger (NCX), and associated regulatory proteins play an essential role in pacemaker automaticity (20)(21)(22)(23). Deletion of Ryr2 or Ncx1 leads to early embryonic lethality and substantial impairment in pacemaker function (22,24).…”

Section: Introductionmentioning

confidence: 99%

Transcription factor ISL1 is essential for pacemaker development and function

Liang¹,

Zhang²,

Cattaneo³

et al. 2015

J. Clin. Invest.

125

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(X. Liang).Statistics. Data are presented as mean ± SEM, and a 2-tailed t test was used for 2-group comparisons. Differences were considered statistically significant at a value of P < 0.05.Study approval. All the experiments involving mice were carried out in accordance with protocols approved by the Institutional Animal Care and Use Committee of USCD (A3033-01) and by the Animal Committee of Tongji University School of Medicine (TJmed-010-10).

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“…Synchronized states in SPCO models map onto steady-state wave fronts of our stochastic model. We note that embryonic CMs spontaneously contract in periodic manner (3,4). In the beating embryonic heart, the wave front is initiated at the atrial end of the heart tube by CMs that contract at a higher frequency.…”

Section: Discussion Mechanical Signaling Robustly Explains Strong Depmentioning

confidence: 84%

“…Although embryonic CMs beat spontaneously (3,4), they would contract with random phases in the absence of a coordinating signal. A number of studies have shown that embryonic, neonatal, and adult CMs are sensitive to mechanical cues (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Mechanical signaling coordinates the embryonic heartbeat

Chiou

Rocks

Chen

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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In the beating heart, cardiac myocytes (CMs) contract in a coordinated fashion, generating contractile wave fronts that propagate through the heart with each beat. Coordinating this wave front requires fast and robust signaling mechanisms between CMs. The primary signaling mechanism has long been identified as electrical: gap junctions conduct ions between CMs, triggering membrane depolarization, intracellular calcium release, and actomyosin contraction. In contrast, we propose here that, in the early embryonic heart tube, the signaling mechanism coordinating beats is mechanical rather than electrical. We present a simple biophysical model in which CMs are mechanically excitable inclusions embedded within the extracellular matrix (ECM), modeled as an elastic-fluid biphasic material. Our model predicts strong stiffness dependence in both the heartbeat velocity and strain in isolated hearts, as well as the strain for a hydrogel-cultured CM, in quantitative agreement with recent experiments. We challenge our model with experiments disrupting electrical conduction by perfusing intact adult and embryonic hearts with a gap junction blocker, β-glycyrrhetinic acid (BGA). We find this treatment causes rapid failure in adult hearts but not embryonic hearts-consistent with our hypothesis. Last, our model predicts a minimum matrix stiffness necessary to propagate a mechanically coordinated wave front. The predicted value is in accord with our stiffness measurements at the onset of beating, suggesting that mechanical signaling may initiate the very first heartbeats. mechanotransduction | excitable media | cardiac development | heartbeat | reaction-diffusion

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Intracellular Ca2+ Oscillations, a Potential Pacemaking Mechanism in Early Embryonic Heart Cells

Cited by 82 publications

References 47 publications

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Emerging roles of inositol 1,4,5-trisphosphate signaling in cardiac myocytes

Transcription factor ISL1 is essential for pacemaker development and function

Mechanical signaling coordinates the embryonic heartbeat

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