Nuclear Ca2+ regulates cardiomyocyte function

Guatimosim, Sílvia; Amaya, Maria Jimena; Guerra, Mateus T.; Aguiar, Carla; Góes, Alfredo M.; Gómez-Viquez, Norma Leticia; Rodrigues, Michele Ângela; Gomes, Dawidson Assis; Martins-Cruz, Juliana; Lederer, W. Jonathan; Leite, M. Fátima

doi:10.1016/j.ceca.2007.11.016

Cited by 72 publications

(93 citation statements)

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“…4B). In accordance with these data, the presence of a diffuse intracellular distribution of RyRs in neonatal cardiac cells has been previously reported by immunocytochemistry (28,29).…”

Section: Pozzan@unipditsupporting

confidence: 76%

Unique characteristics of Ca ²⁺ homeostasis of the trans -Golgi compartment

Lissandron

Podini

Pizzo

et al. 2010

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

114

127

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Taking advantage of a fluorescent Ca 2+ indicator selectively targeted to the trans -Golgi lumen, we here demonstrate that its Ca 2+ homeostatic mechanisms are distinct from those of the other Golgi subcompartments: ( i ) Ca 2+ uptake depends exclusively on the activity of the secretory pathway Ca 2+ ATPase1 (SPCA1), whereas the sarco-endoplasmic reticulum Ca 2+ ATPase (SERCA) is excluded; ( ii ) IP 3 generated by receptor stimulation causes Ca 2+ uptake rather than release; ( iii ) Ca 2+ release can be triggered by activation of ryanodine receptors in cells endowed with robust expression of the latter channels (e.g., in neonatal cardiac myocyte). Finally, we show that, knocking down the SPCA1, and thus altering the trans -Golgi Ca 2+ content, specific functions associated with this subcompartment, such as sorting of proteins to the plasma membrane through the secretory pathway, and the structure of the entire Golgi apparatus are dramatically altered.

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“…4B). In accordance with these data, the presence of a diffuse intracellular distribution of RyRs in neonatal cardiac cells has been previously reported by immunocytochemistry (28,29).…”

Section: Pozzan@unipditsupporting

confidence: 76%

Unique characteristics of Ca ²⁺ homeostasis of the trans -Golgi compartment

Lissandron

Podini

Pizzo

et al. 2010

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

114

127

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“…Almost all studies that examined either the distribution of IP 3 Rs, or the spatial pattern of IP 3 -evoked Ca 2+ signals, have reported that the channels are largely expressed in close proximity to the nucleus in neonatal cells [102,103,[106][107][108]. This is unlike RyRs, which have a more widespread expression pattern in neonatal cells [102].…”

Section: Ip 3 Signaling In Cardiac Developmentmentioning

confidence: 99%

“…However, the concept that IP 3 Rs impact specifically on nuclear Ca 2+ signaling is gaining momentum. Numerous recent reports examining Ca 2+ signaling in neonatal [103,108,109,157], atrial [71,72,137] and ventricular myocytes [140] have demonstrated specific effects of IP 3 -generating agonists or IP 3 itself on nucleoplasmic Ca 2+ signals. Coupling these data with the observations that IP 3 is necessary for some forms of hypertrophy [109,157,158] raises the possibility that IP 3 Rs are key regulators of cardiac myocyte gene transcription and fate.…”

Section: Ip 3 Signaling In Ventricular Myocytesmentioning

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

168

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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“…RyRs are therefore considered to be the main Ca 2+ -release channel in the heart. However, cardiac myocytes also express InsP 3 Rs , and recent studies of neonatal (Garcia et al, 2004;Guatimosim et al, 2008;Luo et al, 2008b;Luo et al, 2006), atrial Kockskamper et al, 2008a;Zima et al, 2007) and ventricular myocytes (Higazi et al, 2009; demonstrated that InsP 3 -generating agonists, or InsP 3 itself, have specific effects on nucleoplasmic Ca 2+ signals. Indeed, it appears that a substantial proportion of InsP 3 Rs in neonatal and adult cardiomyocytes is expressed on membranes close to the nucleus or on the NE (Bare et al, 2005;Higazi et al, 2009;Liu et al, 2001) (Fig.…”

Section: Measuring Nuclear Ca 2+ Signals: Key Considerationsmentioning

confidence: 99%

An update on nuclear calcium signalling

Bootman

Fearnley

Smyrnias

et al. 2009

Journal of Cell Science

184

187

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Over the past 15 years or so, numerous studies have sought to characterise how nuclear calcium (Ca 2+ ) signals are generated and reversed, and to understand how events that occur in the nucleoplasm influence cellular Ca 2+ activity, and vice versa. In this Commentary, we describe mechanisms of nuclear Ca 2+ signalling and discuss what is known about the origin and physiological significance of nuclear Ca 2+ transients. In particular, we focus on the idea that the nucleus has an autonomous Ca 2+ signalling system that can generate its own Ca 2+ transients that modulate processes such as gene transcription. We also discuss the role of nuclear pores and the nuclear envelope in controlling ion flux into the nucleoplasm. Journal of Cell Science 2338(which would cause its nuclear export) and through a physical interaction that occludes a nuclear-export sequence (NES) in the NFAT protein.An example of a nuclear-localised transcription factor that is regulated by both nuclear and cytosolic Ca 2+ signals is cyclic AMP response element-binding protein (CREB). The signalling mechanisms that underlie CREB activation have been worked out particularly well in neurons, in which it has been established that depolarisation leads to the rapid phosphorylation of CREB on Ser133 by Ca 2+ -calmodulin-dependent kinase IV, which provides a necessary, but not sufficient, signal for CREB-mediated gene transcription (Dolmetsch et al., 2001). The triggering event is an increase in cytosolic Ca 2+ levels in the immediate vicinity of L-type Ca 2+ channels or N-methyl-D-aspartate receptors that are found in the synapse, at a site that is distal to the nucleus (Shaywitz and Greenberg, 1999). As CREB is only found in the nucleus, the phosphorylation of Ser133 is mediated by one of several Ca 2+ -sensitive signal transduction cascades that convey information from the remote synapses into the nucleus. In the nucleus, phosphorylated CREB binds additional proteins to form a transcriptionally active complex (Shaywitz and Greenberg, 1999). Although the synaptic Ca 2+ signal does not need to propagate to the nucleus to induce phosphorylation of Ser133 on CREB, an increase in the level of nuclear Ca 2+ is required for CREB-mediated gene transcription to occur. This is because additional Ca 2+ -dependent phosphorylation of CREB and its co-activators is required (Chawla et al., 1998;Kornhauser et al., 2002). Indeed, nuclear injection of an artificial Ca 2+ buffer prevents CREB-mediated gene transcription, but not transcription induced by the serum-response element, which is sensitive to cytosolic Ca 2+ buffering (Hardingham et al., 1997).Another well-known target of nuclear Ca 2+ signalling is the transcriptional regulator downstream regulatory element antagonist modulator (DREAM). It is well established that DREAM represses the expression of prodynorphin, an opiate-receptor precursor, and that mice that lack DREAM have a constitutive analgesic condition (Cheng et al., 2002). DREAM contains four Ca 2+ -binding EF hands (a widely expressed structural mo...

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Nuclear Ca2+ regulates cardiomyocyte function

Cited by 72 publications

References 50 publications

Unique characteristics of Ca ²⁺ homeostasis of the trans -Golgi compartment

Unique characteristics of Ca ²⁺ homeostasis of the trans -Golgi compartment

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

An update on nuclear calcium signalling

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Nuclear Ca2+ regulates cardiomyocyte function

Cited by 72 publications

References 50 publications

Unique characteristics of Ca 2+ homeostasis of the trans -Golgi compartment

Unique characteristics of Ca 2+ homeostasis of the trans -Golgi compartment

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

An update on nuclear calcium signalling

Contact Info

Product

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About

Unique characteristics of Ca ²⁺ homeostasis of the trans -Golgi compartment

Unique characteristics of Ca ²⁺ homeostasis of the trans -Golgi compartment