Cardiac inositol 1,4,5-trisphosphate receptors

Garcia, M. Iveth; Boehning, Darren

doi:10.1016/j.bbamcr.2016.11.017

Cited by 33 publications

(22 citation statements)

References 109 publications

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“…These findings indicate that IP3R-mediated Ca 2+ release and SERCA-mediated SR Ca 2+ uptake are one of the major compensatory mechanisms for Ca 2+ handling in human CMs when the RYR2 function is lost. Future studies should investigate whether IP3R-dependent mitochondrial Ca 2+ flux modulates spontaneous electrical activity in human RYR2 −/− -iPSC-CMs and whether IP3R-mediated nuclear Ca 2+ signaling is involved in the activation of nuclear signal transduction for CM survival (Garcia and Boehning, 2017). Previous studies demonstrated that the store-operated calcium entry (SOCE) is present in embryonic cardiomyocytes and induces significant rise in Ca 2+ entry when the depletion of SR Ca 2+ stores occurs (Huang et al, 2006;Avila-Medina et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

IP3R-Mediated Compensatory Mechanism for Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Cardiac Ryanodine Receptor Deficiency

Luo

Künzel

et al. 2020

Front. Cell Dev. Biol.

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In adult cardiomyocytes (CMs), the type 2 ryanodine receptor (RYR2) is an indispensable Ca 2+ release channel that ensures the integrity of excitation-contraction coupling, which is fundamental for every heartbeat. However, the role and importance of RYR2 during human embryonic cardiac development are still poorly understood. Here, we generated two human induced pluripotent stem cell (iPSC)-based RYR2 knockout (RYR2 −/−) lines using the CRISPR/Cas9 gene editing technology. We found that RYR2 −/−-iPSCs could differentiate into CMs with the efficiency similar to control-iPSCs (Ctrl-iPSCs); however, the survival of iPSC-CMs was markedly affected by the lack of functional RYR2. While Ctrl-iPSC-CMs exhibited regular Ca 2+ handling, we observed significantly reduced frequency and intense abnormalities of Ca 2+ transients in RYR2 −/−-iPSC-CMs. Ctrl-iPSC-CMs displayed sensitivity to extracellular Ca 2+ ([Ca 2+ ] o) and caffeine in a concentration-dependent manner, while RYR2 −/−-iPSC-CMs showed inconsistent reactions to [Ca 2+ ] o and were insensitive to caffeine, indicating there is no RYR2mediated Ca 2+ release from the sarcoplasmic reticulum (SR). Instead, compensatory mechanism for calcium handling in RYR2 −/−-iPSC-CMs is partially mediated by the inositol 1,4,5-trisphosphate receptor (IP3R). Similar to Ctrl-iPSC-CMs, SR Ca 2+ refilling in RYR2 −/−-iPSC-CMs is mediated by SERCA. Additionally, RYR2 −/−-iPSC-CMs showed a decreased beating rate and a reduced peak amplitude of L-type Ca 2+ current. These findings demonstrate that RYR2 is not required for CM lineage commitment but is important for CM survival and contractile function. IP3R-mediated Ca 2+ release is one of the major compensatory mechanisms for Ca 2+ cycling in human CMs with the RYR2 deficiency.

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Section: Discussionmentioning

confidence: 99%

IP3R-Mediated Compensatory Mechanism for Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Cardiac Ryanodine Receptor Deficiency

Luo

Künzel

et al. 2020

Front. Cell Dev. Biol.

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“…However, the majority of the studies on the role of IP 3 Rs in hypertrophy have focused solely on IP 3 R-2, despite the fact that the other two isoforms are also expressed in the heart [8, 17, 20]. We now show that all three IP 3 R channels are expressed at readily detectable levels in cardiomyocytes in both rodent and human heart.…”

Section: Discussionmentioning

confidence: 68%

“…As such, it is still unclear whether IP 3 R channels are significant contributors to cardiac physiology and pathologic remodeling such as hypertrophy [19]. It has been shown that all three IP 3 R isoforms, at least at the mRNA level, are expressed in the heart of humans and mice [8, 20]. This opens the question of whether IP 3 R-1 and -3 are able to functionally compensate for IP 3 R-2 deficiencies in these models.…”

Section: Introductionmentioning

confidence: 99%

Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors

Garcia

Karlstaedt

Chen

et al. 2017

Journal of Molecular and Cellular Cardiology

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Calcium plays an integral role to many cellular processes including contraction, energy metabolism, gene expression, and cell death. The inositol 1, 4, 5-trisphosphate receptor (IP3R) is a calcium channel expressed in cardiac tissue. There are three IP 3R isoforms encoded by separate genes. In the heart, the IP3R-2 isoform is reported to being most predominant with regards to expression levels and functional significance. The functional roles of IP3R-1 and IP3R-3 in the heart are essentially unexplored despite measureable expression levels. Here we show that all three IP3Rs isoforms are expressed in both neonatal and adult rat ventricular cardiomyocytes, and in human heart tissue. The three IP3R proteins are expressed throughout the cardiomyocyte sarcoplasmic reticulum. Using isoform specific siRNA, we found that expression of all three IP 3R isoforms are required for hypertrophic signaling downstream of endothelin-1 stimulation. Mechanistically, IP 3Rs specifically contribute to activation of the hypertrophic program by mediating the positive inotropic effects of endothelin-1 and leading to downstream activation of nuclear factor of activated T-cells. Our findings highlight previously unidentified functions for IP 3R isoforms in the heart with specific implications for hypertrophic signaling in animal models and in human disease.

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“…Increasing numbers of IP 3 Rs and in particular 'leaky' IP 3 Rs , as would result from increased diastolic Ca 2+ concentration, lead to increased spark initiation frequency. This suggests that the increase in IP 3 R expression could be a compensatory mechanism to dyad uncoupling from electrical activity in disease [49].…”

Section: Model Assumptions and Their Implicationsmentioning

confidence: 97%

IP₃R activity increases frequency of RyR-mediated sparks by elevating dyadic Ca²⁺

Tilūnaitė

Ladd

Hunt

et al. 2020

Preprint

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Calcium plays critical roles in cardiac cells, coupling electrical excitation to mechanical contraction with each heartbeat, while simultaneously mediating biochemical signals that regulate cell growth. While ryanodine receptors (RyRs) are fundamental to generation of elementary calcium release events (sparks) and global calcium elevations that underlie excitation-contraction coupling (ECC), calcium release via inositol 1,4,5-trisphosphate receptors (IP3Rs) is also reported in cardiomyocytes. IP3R calcium release modifies ECC as well as contributing to downstream regulation of hypertrophic gene expression. Recent studies suggest that proximal localisation of IP3Rs with RyRs contributes to their ability to modify Ca2+ handling during ECC. Here we aim to determine the mechanism by which IP3Rs modify Ca2+ handling in cardiomyocytes. We develop a mathematical model incorporating the stochastic behaviour of receptor opening that allows for the parametric tuning of the system to reveal the impact of IP3Rs on spark activation. By testing multiple spark initiation mechanisms, we find that Ca2+ release via IP3Rs result in increased propensity for spark initiation within the cardiac dyad. Our simulations suggest that opening of IP3Rs elevates Ca2+ within the dyad, which increase the probability of spark initiation. Finally, we find that while increasing the number of IP3Rs increases the probability of spark formation, it has little effect on spark amplitude, duration, or overall shape. Our study therefore suggests that IP3R play a critical role in modulating Ca2+ signaling for excitation contraction coupling.

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Cardiac inositol 1,4,5-trisphosphate receptors

Cited by 33 publications

References 109 publications

IP3R-Mediated Compensatory Mechanism for Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Cardiac Ryanodine Receptor Deficiency

IP3R-Mediated Compensatory Mechanism for Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Cardiac Ryanodine Receptor Deficiency

Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors

IP₃R activity increases frequency of RyR-mediated sparks by elevating dyadic Ca²⁺

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Cardiac inositol 1,4,5-trisphosphate receptors

Cited by 33 publications

References 109 publications

IP3R-Mediated Compensatory Mechanism for Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Cardiac Ryanodine Receptor Deficiency

IP3R-Mediated Compensatory Mechanism for Calcium Handling in Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes With Cardiac Ryanodine Receptor Deficiency

Functionally redundant control of cardiac hypertrophic signaling by inositol 1,4,5-trisphosphate receptors

IP3R activity increases frequency of RyR-mediated sparks by elevating dyadic Ca2+

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IP₃R activity increases frequency of RyR-mediated sparks by elevating dyadic Ca²⁺