Nuclear calcineurin is a sensor for detecting Ca2+ release from the nuclear envelope via IP3R

Olivares‐Florez, Silvana; Czolbe, Martin; Riediger, Fabian; Seidlmayer, Lea K.; Williams, Tatjana; Nordbeck, Peter; Strasen, Jörn; Glocker, Cristina; Jänsch, Monique; Eder-Negrin, Petra; Arias-Loza, Paula; Mühlfelder, Melanie; Plačkić, Jelena; Heinze, Katrin G.; Molkentin, Jeffery D.; Engelhardt, Stefan; Kockskämper, Jens; Ritter, Oliver

doi:10.1007/s00109-018-1701-2

Cited by 18 publications

(24 citation statements)

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“…The physiological and pathological relevance of nuclear Ca signaling in cardiac myocytes and its regulation have long been elusive. With recent studies showing nuclear Ca to play a major role in transcriptional control and—if impaired—to induce cardiac remodeling and hypertrophy (Ljubojevic et al, 2014; Ljubojevic and Bers, 2015; Plačkić et al, 2016; Dewenter et al, 2017; Olivares-Florez et al, 2018), it is important to elucidate the cellular mechanisms of nuclear Ca handling. In this study, we identify the cytoplasmic CaT and—as a novel regulator—SERCA activity as the major determinants of the systolic CaT in the nucleus, whereas modulation of PN Ca stores is much less important.…”

Section: Discussionmentioning

confidence: 99%

“…Nuclear Ca levels are directly involved in ET coupling. The known Ca-dependent targets that initiate the pro-hypertrophic cascades (CaMKII and calcineurin) are found in the nucleus (Heineke and Molkentin, 2006; Olivares-Florez et al, 2018). Hence, nuclear Ca may be suspected to play a crucial role in the pathogenesis of cardiac hypertrophy and ultimately HF.…”

Section: Introductionmentioning

confidence: 99%

“…Hence, nuclear Ca may be suspected to play a crucial role in the pathogenesis of cardiac hypertrophy and ultimately HF. Moreover, recent studies have shown, that during development of hypertrophy and HF specific alterations to the nuclear structure and function may occur including alterations of nuclear size, of number and density of NE invaginations and of perinuclear expression levels of receptors and channels involved in Ca homeostasis, such as IP 3 receptors, RyRs and SERCA (Ljubojevic et al, 2014; Plačkić et al, 2016; Olivares-Florez et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

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SERCA Activity Controls the Systolic Calcium Increase in the Nucleus of Cardiac Myocytes

Kiess

Kockskämper

2019

Front. Physiol.

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In cardiomyocytes, nuclear calcium is involved in regulation of transcription and, thus, remodeling. The cellular mechanisms regulating nuclear calcium, however, remain elusive. Therefore, the aim of this study was to identify and characterize the factors that regulate nuclear calcium in cardiomyocytes. We focused on the roles of (1) the cytoplasmic calcium transient (CaT), (2) the sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA), and (3) intracellular calcium stores for nuclear calcium handling. Experiments were performed on rat ventricular myocytes loaded with Fluo-4/AM. Subcellularly resolved CaTs were visualized using confocal microscopy. The cytoplasmic CaT was varied by reducing extracellular calcium (from 1.5 to 0.3 mM) or by exposure to isoprenaline (ISO, 10 nM). SERCA was blocked by thapsigargin (5 μM). There was a strict linear dependence of the nucleoplasmic CaT on the cytoplasmic CaT over a wide range of calcium concentrations. Increasing SERCA activity impaired, whereas decreasing SERCA activity augmented the systolic calcium increase in the nucleus. Perinuclear calcium store load, on the other hand, did not change with either 0.3 mM calcium or ISO and was not a decisive factor for the nucleoplasmic CaT. The results indicate, that the nucleoplasmic CaT is determined largely by the cytoplasmic CaT via diffusion of calcium through nuclear pores. They identify perinuclear SERCA activity, which limits the systolic calcium increase in the nucleus, as a novel regulator of the nuclear CaT in cardiac myocytes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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SERCA Activity Controls the Systolic Calcium Increase in the Nucleus of Cardiac Myocytes

Kiess

Kockskämper

2019

Front. Physiol.

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“…In healthy adult rat ventricular myocytes (ARVMs), various effects of IP 3 on global Ca 2+ transients associated with ECC have been described, summarised in Table 1. While application of GPCR agonists that stimulate IP 3 generation produces robust effects on ECC associated IP 3 transients and contraction, the direct contribution of IP 3 to these actions varies between studies (17,(20)(21)(22)(23)(24). For example, in rabbit the effect of ET-1 on Ca 2+ transient amplitude is sensitive to the IP 3 R inhibitor 2-APB (22), whereas in healthy rats IP 3 R inhibition with 2-APB was without effect (25).…”

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confidence: 99%

Ca2+ Release via IP3 Receptors Shapes the Cardiac Ca2+ Transient for Hypertrophic Signaling

Hunt

Tilūnaitė

Bass

et al. 2020

Biophysical Journal

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Calcium (Ca 2+ ) plays a central role in mediating both contractile function and hypertrophic signalling in ventricular cardiomyocytes. L-type Ca 2+ channels trigger release of Ca 2+ from ryanodine receptors (RyRs) for cellular contraction, while signalling downstream of Gq coupled receptors stimulates Ca 2+ release via inositol 1,4,5-trisphosphate receptors (IP 3 Rs), engaging hypertrophic signalling pathways. Modulation of the amplitude, duration, and duty cycle of the cytosolic Ca 2+ contraction signal, and spatial localisation, have all been proposed to encode this hypertrophic signal. Given current knowledge of IP 3 Rs, we develop a model describing the effect of functional interaction (cross-talk) between RyR and IP 3 R channels on the Ca 2+ transient, and examine the sensitivity of the Ca 2+ transient shape to properties of IP 3 R activation. A key result of our study is that IP 3 R activation increases Ca 2+ transient duration for a broad range of IP 3 R properties, but the effect of IP 3 R activation on Ca 2+ transient amplitude is dependent on IP 3 concentration. Furthermore we demonstrate that IP 3 -mediated Ca 2+ release in the cytosol increases the duty cycle of the Ca 2+ transient, the fraction of the cycle for which [Ca 2+ ] is elevated, across a broad range of parameter values and IP 3 concentrations. When coupled to a model of downstream transcription factor (NFAT) activation, we demonstrate that there is a high correspondence between the Ca 2+ transient duty cycle and the proportion of activated NFAT in the nucleus. These findings suggest increased cytosolic Ca 2+ duty cycle as a plausible mechanism for IP 3 -dependent hypertrophic signalling via Ca 2+ -sensitive transcription factors such as NFAT in ventricular cardiomyocytes. SIGNIFICANCE Many studies have identified a role for IP 3 R-mediated Ca 2+ signalling in cardiac hypertrophy, however the mechanism by which this signal is communicated within the cardiomyocyte remains unclear. We present a mathematical model of functional interactions between RyR and IP 3 R channels. We show that IP 3 -mediated Ca 2+ release is capable of providing a modest increase to the duty cycle of the calcium signal, which has been shown experimentally to lead to NFAT activation, and hence hypertrophic signalling. Through a parameter sensitivity analysis we demonstrate that the duty cycle is increased with IP 3 over a broad parameter regime, indicating that this mechanism is robust, and we show that an increase in Ca 2+ duty cycle increases nuclear NFAT activation. These findings suggest a plausible mechanism for IP3R-dependent hypertrophic signalling in cardiomyocytes. INTRODUCTIONCalcium is a universal second messenger that plays a role in controlling many cellular processes across a wide variety of cell types; ranging from fertilisation, cell contraction, and cell growth, to cell death (1, 2). Precisely how Ca 2+ fulfills each of these † These authors contributed equally to the supervision of this work.

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“…Finally, recent data suggest that nuclear translocation of calcineurin might be required for full transcriptional activity of NFAT. Such nuclear calcineurin can act as an intranuclear calcium sensor in cardiac hypertrophy, detecting local calcium release via IP3R (231).…”

Section: Calcineurin-dependent Transcriptional Regulationmentioning

confidence: 99%

Integrative computational modeling of calcium handling and cardiac arrhythmias

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Nuclear calcineurin is a sensor for detecting Ca2+ release from the nuclear envelope via IP3R

Cited by 18 publications

References 23 publications

SERCA Activity Controls the Systolic Calcium Increase in the Nucleus of Cardiac Myocytes

SERCA Activity Controls the Systolic Calcium Increase in the Nucleus of Cardiac Myocytes

Ca2+ Release via IP3 Receptors Shapes the Cardiac Ca2+ Transient for Hypertrophic Signaling

Integrative computational modeling of calcium handling and cardiac arrhythmias

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