Extensive Ca2+ leak through K4750Q cardiac ryanodine receptors caused by cytosolic and luminal Ca2+ hypersensitivity

Uehara, Akira; Murayama, Takashi; Yasukochi, Midori; Fill, Michael; Horie, Minoru; Okamoto, Tomoyoshi; Matsuura, Yoshiharu; Uehara, Kiyoko; Fujimoto, Takahiro; Sakurai, Takashi; Kurebayashi, Nagomi

doi:10.1085/jgp.201611624

Cited by 48 publications

(100 citation statements)

References 52 publications

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“…Most of these mutations are clustered in three different regions of RyR sequence, which are located in: N-terminal region (first ∼600 amino acids), a central region (amino acids ∼2100–2500), and the C-terminal area (amino acid ∼3900–end). Mutations in the C-terminal area of RyR2 (including EF-hand and pore domains) have been recently related to Ca 2+ sensing mechanisms (Jiang et al, 2004; Uehara et al, 2017). Three mutations in this area (N4104K, R4496C, and N4895D) have been shown to decrease the threshold for RyR2 activation by SR luminal Ca 2+ , thus affecting overload-induced SR Ca 2+ release (Jiang et al, 2004).…”

Section: Disease Linked To Genetic Impairments Of Ca2+ Sensing Proteinsmentioning

confidence: 99%

“…Three mutations in this area (N4104K, R4496C, and N4895D) have been shown to decrease the threshold for RyR2 activation by SR luminal Ca 2+ , thus affecting overload-induced SR Ca 2+ release (Jiang et al, 2004). A single mutation at K4750Q in RyR2 causes hypersensitization to activation by either [Ca 2+ ] c or SR luminal Ca 2+ as well as loss of cytosolic Ca 2+ /Mg 2+ -mediated inactivation and leads to a very severe clinical phenotype (Sugiyasu et al, 2009; Uehara et al, 2017). Mutations in RyR2 are linked to catecholaminergic polymorphic ventricular tachycardia (Priori et al, 2001), whereas RyR1 mutations are associated with central core disease (Zhang et al, 1993) and malignant hyperthermia (MacLennan, 1992).…”

Section: Disease Linked To Genetic Impairments Of Ca2+ Sensing Proteinsmentioning

confidence: 99%

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Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling

2017

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Summary Ca2+ is a ubiquitous intracellular messenger that controls diverse cellular functions but can become toxic and cause cell death. Selective control of specific targets depends on spatio-temporal patterning of the calcium signal and decoding it by multiple, tunable and often strategically positioned Ca2+ sensing elements. Ca2+ is detected by specialized motifs on proteins, which have been biochemically characterized decades ago. However, the field of Ca2+ sensing has been reenergized by recent progress in fluorescent technology, genetics and cryo-EM. These approaches exposed local Ca2+ sensing mechanisms inside organelles and at the organellar interfaces, revealed how Ca2+ binding might work to open some channels, and identified human mutations and disorders linked to a variety of Ca2+ sensing proteins. We here, attempt to place these new developments in the context of intracellular calcium homeostasis and signaling.

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Section: Disease Linked To Genetic Impairments Of Ca2+ Sensing Proteinsmentioning

confidence: 99%

Section: Disease Linked To Genetic Impairments Of Ca2+ Sensing Proteinsmentioning

confidence: 99%

Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling

2017

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“…WT cells showed spontaneous Ca 2+ oscillations with corresponding periodic decrease in [Ca 2+ ]ER in normal Krebs solution ( Figure 4A Left), as reported previously. 9,19,20 Application of 10 mmol/L caffeine induced transient Ca 2+ oscillations with amplitude similar to spontaneous oscillations ( Figure 4A). The R169Q cells showed very small and more frequent Ca 2+ oscillations in normal Krebs solution (Figure 4A Right,B).…”

Section: Functional Analysismentioning

confidence: 66%

Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a <i>Ryanodine Receptor Type 2</i> Missense Mutation

Nozaki

Kato

Uike

et al. 2020

Circ J

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Background: Left ventricular non-compaction (LVNC) is a cardiomyopathy characterized by prominent trabeculae and intertrabecular recesses. We present the cases of 3 girls with the same ryanodine receptor type 2 (RYR2) mutation who had phenotypes of both catecholaminergic polymorphic ventricular tachycardia (CPVT) and LVNC. Methods and Results: Clinical characteristics and genetic background of the 3 patients were analyzed retrospectively. Age at onset was 5, 6, and 7 years, respectively. Clinical presentation included syncope during exercise in all 3 patients and cardiac arrest in 2 patients. LVNC diagnosis was confirmed on echocardiography according to previously defined criteria. Exercise stress testing provoked ventricular arrhythmia in two of the patients. Beta-blockers (n=3) and flecainide (n=2) were given, and an implantable cardioverter defibrillator was used in 1 patient. Genotyping identified the same RYR2-R169Q missense mutation and no other CPVT-or LVNC-related gene mutations. Functional analysis of the mutation using HEK293 cells with single-cell Ca 2+ imaging and [ 3 H]ryanodine binding analysis, indicated a gain of function: a reduced threshold for overload-induced Ca 2+ release from the sarcoplasmic reticulum and increased fractional Ca 2+ release. Conclusions: The rare association of LVNC and CPVT phenotypes with RYR2 mutations is less likely to be coincidental. Screening for life-threatening arrhythmias using exercise or pharmacologic stress tests is recommended in LVNC patients to prevent sudden cardiac death in those with preserved LV function.

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“…Ryanodine channels that deplete the calcium stores in response to ryanodine are ER resident leak channels, RyRs respond to ryanodine at low concentration and caffeine. Ryanodine receptors have been extensively investigated in eukaryotic cells (39,40,41,42). Fig 4 d represents the calcium response of 100 µM and 10 mM caffeine.…”

Section: Establishment Of Ted Based Calcium Imaging In Microsomesmentioning

confidence: 99%

Targeted Esterase induced Dye loading supports Calcium Imaging in Eukaryotic Cell-Free Systems

Dhandapani

Dondapati

Zemella

et al. 2020

Preprint

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Calcium imaging is an important functional tool for addressing ion channels, transporters and pumps for drug screening in living cells. Depicted eukaryotic cell-free systems utilize microsomes, derived from endoplasmic reticulum to incorporate the synthesized membrane proteins. Absence or inadequate amount of carboxylesterase in the endoplasmic reticulum of eukaryotic cells, which is necessary to cleave the acetoxymethyl ester moiety of the chemical calcium indicators, advocates the hindrance to perform calcium imaging in microsomes. In this work, we try to overcome this drawback and adapt the cell-based calcium imaging principle to a cell-free protein synthesis platform. Carboxylesterase synthesized in a Spodoptera frugiperda Sf21 lysate translation system is established as a viable calcium imaging tool and hTRPV1 is used as a model channel protein to demonstrate the realization of this concept.

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Extensive Ca2+ leak through K4750Q cardiac ryanodine receptors caused by cytosolic and luminal Ca2+ hypersensitivity

Cited by 48 publications

References 52 publications

Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling

Intracellular Ca2+ Sensing: Its Role in Calcium Homeostasis and Signaling

Co-Phenotype of Left Ventricular Non-Compaction Cardiomyopathy and Atypical Catecholaminergic Polymorphic Ventricular Tachycardia in Association With R169Q, a <i>Ryanodine Receptor Type 2</i> Missense Mutation

Targeted Esterase induced Dye loading supports Calcium Imaging in Eukaryotic Cell-Free Systems

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