Response to Letter Regarding Article “Inositol 1,4,5-Trisphosphate Receptors and Human Left Ventricular Myocytes”

Signore, Sergio; Sorrentino, Andrea; Ferreira-Martins, João; Kannappan, Ramaswamy; Shafaie, Mehrdad; Ben, Fabio Del; Isobe, Kazuya; Arranto, Christian; Wybieralska, Ewa; Webster, Andrew; Sanada, Fumihiro; Ogórek, Barbara; Zheng, Hui; Liu, Xiaoxia; Monte, Federica del; D’Alessandro, David A.; Oriyanhan, Wnimunk; Michler, Robert E.; Hosoda, Toru; Goichberg, Polina; Leri, Annarosa; Kajstura, Jan; Anversa, Piero; Rota, Marcello

doi:10.1161/circulationaha.114.009347

Cited by 7 publications

(13 citation statements)

References 5 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…S7 and are consistent with Bondarenko et al [5]. The resulting AP has an APD 90 (time to 90% recovery of depolarization) of ~40 ms, which is consistent with whole cell ruptured patch clamp and micro-electrode recordings of mouse APs [64,65]. Additional [Ca 2+ ] i and AP dynamics are shown in Figs.…”

Section: Resultssupporting

confidence: 87%

Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling

Wescott

Jafri

Lederer

et al. 2016

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

Calcium-induced calcium release is the principal mechanism that triggers the cell-wide [Ca2+]i transient that activates muscle contraction during cardiac excitation-contraction coupling (ECC). Here, we characterize this process in mouse cardiac myocytes with a novel mathematical action potential (AP) model that incorporates realistic stochastic gating of voltage-dependent L-type calcium (Ca2+) channels (LCCs) and sarcoplasmic reticulum (SR) Ca2+ release channels (the ryanodine receptors, RyR2s). Depolarization of the sarcolemma during an AP stochastically activates the LCCs elevating subspace [Ca2+] within each of the cell’s 20,000 independent calcium release units (CRUs) to trigger local RyR2 opening and initiate Ca2+ sparks, the fundamental unit of triggered Ca2+ release. Synchronization of Ca2+ sparks during systole depends on the nearly uniform cellular activation of LCCs and the likelihood of local LCC openings triggering local Ca2+ sparks (ECC fidelity). The detailed design and true SR Ca2+ pump/leak balance displayed by our model permits investigation of ECC fidelity and Ca2+ spark fi-delity, the balance between visible (Ca2+ spark) and invisible (Ca2+ quark/sub-spark) SR Ca2+ release events. Excess SR Ca2+ leak is examined as a disease mechanism in the context of “catecholaminergic polymorphic ventricular tachycardia (CPVT)”, a Ca2+-dependent arrhythmia. We find that that RyR2s (and therefore Ca2+ sparks) are relatively insensitive to LCC openings across a wide range of membrane potentials; and that key differences exist between Ca2+ sparks evoked during quiescence, diastole, and systole. The enhanced RyR2 [Ca2+]i sensitivity during CPVT leads to increased Ca2+ spark fidelity resulting in asynchronous systolic Ca2+ spark activity. It also produces increased diastolic SR Ca2+ leak with some prolonged Ca2+ sparks that at times become “metastable” and fail to efficiently terminate. There is a huge margin of safety for stable Ca2+ handling within the cell and this novel mechanistic model provides insight into the molecular signaling characteristics that help maintain overall Ca2+ stability even under the conditions of high SR Ca2+ leak during CPVT. Finally, this model should provide tools for investigators to examine normal and pathological Ca2+ signaling characteristics in the heart.

show abstract

Section: Resultssupporting

confidence: 87%

Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling

Wescott

Jafri

Lederer

et al. 2016

Journal of Molecular and Cellular Cardiology

View full text Add to dashboard Cite

show abstract

“…3). Therefore, these data support the proposal that the activation of IP 3 Rs can somehow initiate spontaneous Ca 2+ fluctuations (8,11,12,18,20), affects the native Ca 2+ activities, and regulates the spontaneous Ca 2+ signaling in resting NRVMs. In heart, three isoforms of IP 3 Rs are found in neonatal and adult ventricles.…”

Section: Discussionsupporting

confidence: 84%

“…In heart, three isoforms of IP 3 Rs are found in neonatal and adult ventricles. However, it is difficult to detect any functional differences between these isoforms because of the much low expression of each isotype in heart (7,8,18,21). Thus we conducted knock-down of all three isoforms concomitantly in NRVMs and found a significant reduction in Ca 2+ transient rate and amplitude in IP 3 R-deficient NRVMs.…”

Section: Discussionmentioning

confidence: 93%

“…To further determine the role of IP 3 Rs in the regulation of native Ca 2+ activity in NRVMs, interferences of IP 3 R1, IP 3 R2, and IP 3 R3 expression with shRNA specific against each isotype expression were performed (see Materials and Methods), as all three isoforms of IP 3 Rs are expressed in neonatal hearts (7,8,10,18). After transfection with all three IP 3 R isotype shRNAs in combination for 48 h, NRVMs exhibited approximately 68% reduction in IP 3 R abundance (Fig.…”

Section: Effect Of Ip 3 R Interference On Ca 2+ Transients In Single mentioning

confidence: 99%

See 1 more Smart Citation

Role of Inositol-1,4,5-Trisphosphate Receptor in the Regulation of Calcium Transients in Neonatal Rat Ventricular Myocytes

et al. 2014

View full text Add to dashboard Cite

Abstract. This study determined the regulatory effect of inositol 1,4,5-trisphosphate receptors (IP 3 Rs) on the basal Ca 2+ transients in cardiomyocytes. In cultured neonatal rat ventricular myocytes (NRVMs) at different densities, we used confocal microscopy to assess the effect of IP 3 Rs on the endogenous spontaneous Ca 2+ oscillations through specific activation of IP 3 Rs with myo-IP 3 hexakis (butyryloxymethyl) ester (IP 3 BM), a membrane permeable IP 3 , and interference of IP 3 R expression with shRNA. We found that NRVMs at the monolayer state displayed coordinated Ca 2+ transients with less rate, shorter duration, and higher amplitude compared to single NRVMs. In addition, monolayer NRVMs exhibited 4 or 10 times more increased Ca 2+ transients in response to phenylephrine, an a-adrenergic receptor agonist, or IP 3 BM than single NRVMs did, while the transient pattern remained unaltered, suggesting that the sensitivity of intracellular Ca 2+ response to IP 3 R activation is different between single and monolayer NRVMs. However, interference of IP 3 R expression with shRNA reduced the frequency and amplitude of the spontaneous Ca 2+ fluctuates similarly in both densities of NRVMs, resembling the effects of ryanodine receptor inhibition by ryanodine or tetracaine. Our findings suggest that IP 3 Rs are involved, in part, in the regulation of native Ca 2+ transients, in profiles of their initiation and Ca 2+ release extent, in developing cardiomyocytes. In addition, caution should be paid in evaluating the behavior of Ca 2+ signaling in primary cultured cardiomyocytes at different densities.

show abstract

“…1,5 Yet, the functional consequences of this coincidence on the electromechanical behavior and transcriptional activity in the failing myocardium remain to be elucidated carefully, by listening to the entire ensemble of InsP3R regulatory mechanisms.…”

mentioning

confidence: 99%

Letter by Heidrich et al Regarding Article, “Inositol 1,4,5-Trisphosphate Receptors and Human Left Ventricular Myocytes”

2014

View full text Add to dashboard Cite

issue of Circulation, this article provides compelling evidence that the G αq -protein-coupled receptor (GPCR)/InsP3R axis plays a critical role in the regulation of cardiomyocyte calcium homeostasis, electric stability, and contractile performance. The authors demonstrate that GPCR agonists generate InsP3, which activates InsP3Rs to liberate calcium from internal stores, resulting in decreased resting membrane potential, prolongation of myocyte action potential, and the occurrence of early afterdepolarizations. These mechanisms cause electric instability and contractile abnormalities.However, when studying the regulation of calcium homeostasis by InsP3Rs in a given system (eg, in cardiomyocytes), listening to the entire orchestra is key to unequivocally hearing all tones and undertones of the concert. InsP3R function is regulated by at least 3 distinct mechanisms: at the point of InsP3 generation, which basically acts as the on/off switch of the channel (eg, by GPCR agonists); at the level of InsP3R protein expression; and by endogenous InsP3R regulators.2 The last regulatory mechanism of InsP3R function we missed being addressed by the authors of this otherwise thoroughly conducted study.We have recently shown that a well-known and extensively studied important endogenous regulator of the InsP3R, chromogranin B (CGB), is expressed in cardiomyocytes.3 CGB, an acidic calcium storage protein, acts as a positive modulator of InsP3R activity. 4 In cardiomyocytes, we showed that CGB functionally interacts with the InsP3R to shape GPCR agonist-driven, InsP3-dependent calcium release from internal stores, being responsible for the differential activation of calcium-dependent transcription factors in cardiomyocyte excitation-transcription coupling.3 Therefore, considering that activation of the GPCR/InsP3R axis in cardiomyocytes potentially has both electromechanical and transcriptional implications, we believe it is important to carefully examine all regulatory mechanisms of InsP3R channel activity possibly being involved within a given system. Otherwise, subtle tones and undertones within the complex cardiomyocyte calcium signaling concert can easily be missed.Signaling specificity of the multifunctional second messenger calcium is achieved by variations in and combinations of the magnitude, frequency, and duration of calcium signals, parameters that are potentially being modified by fine-tuning of InsP3R activity by its endogenous regulators such as CGB. Subtle variations in InsP3-dependent calcium wave patterns may make the difference in beneficial (eg, selective activation of calcium-dependent transcription factors) versus adverse (eg, electric instability) effects of InsP3R activation in cardiomyocytes and the diseased myocardium.When the data of this article are integrated with the data in another recently published study, the CGB/InsP3R interaction may become even more pronounced in the failing human heart, with markedly increased ventricular InsP3R type 2 protein expression paralleling increased CGB expression...

show abstract

Response to Letter Regarding Article “Inositol 1,4,5-Trisphosphate Receptors and Human Left Ventricular Myocytes”

Cited by 7 publications

References 5 publications

Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling

Ryanodine receptor sensitivity governs the stability and synchrony of local calcium release during cardiac excitation-contraction coupling

Role of Inositol-1,4,5-Trisphosphate Receptor in the Regulation of Calcium Transients in Neonatal Rat Ventricular Myocytes

Letter by Heidrich et al Regarding Article, “Inositol 1,4,5-Trisphosphate Receptors and Human Left Ventricular Myocytes”

Contact Info

Product

Resources

About