The arrhythmogenic human HRC point mutation S96A leads to spontaneous Ca2+ release due to an impaired ability to buffer store Ca2+

Zhang, Joe Z.; McLay, Janet C.; Jones, Peter P.

doi:10.1016/j.yjmcc.2014.04.019

Cited by 20 publications

(20 citation statements)

References 46 publications

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“…Consistent with previous researches [7, 28], our study also confirmed that HRC could influence intracellular calcium. While the mechanism for HRC-dependent modulation of [Ca 2+ ] i in HCC cells is still unclear.…”

Section: Discussionsupporting

confidence: 93%

The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1

Liu

Han

et al. 2015

Oncotarget

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The histidine-rich calcium binding protein (HRC) is a regulator of Ca2+-homeostasis. Herein, we found that HRC was frequently upregulated in human hepatocellular carcinoma (HCC) tissues, and its expression was correlated with tumor size and metastasis. Moreover, HRC expression was positively related to the metastatic potential of HCC cell lines. Knockdown of HRC suppressed cell invasion and migration in vitro, whereas ectopic expression of HRC resulted in increased cell invasion and migration in vitro and intrahepatic and lung metastasis in vivo. Interestingly, the pro-invasion and pro-migration effects of HRC were associated with focal adhesion turnover, which was a consequence of FAK phosphorylation. Further experiments showed that HRC induced phospho-FAK, focal adhesion turnover and cell migration through Ca2+/CaM singaling. We found that HRC increased [Ca2+]i by inhibiting the expression of SERCA2. In addition, upregulation of HRC in HCC was attributed to SATB1, which is known to promote HCC metastasis. Ectopic expression of SATB1 enhanced HRC gene transcription by activating AP-1 in mainly a JNK-dependent manner. Our findings highlight HRC as a potential therapeutic target for HCC treatment.

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Section: Discussionsupporting

confidence: 93%

The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1

Liu

Han

et al. 2015

Oncotarget

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“…Measurements of cytosolic Ca 2þ were conducted in stable, inducible HEK293 cells expressing RyR2 as previously described (21). RyR2 expression was induced~18 h before measurements commenced via the addition of tetracycline (0.1 mg/ml).…”

Section: Cytosolic Ca 2þ Measurementsmentioning

confidence: 99%

Oxidation of RyR2 Has a Biphasic Effect on the Threshold for Store Overload-Induced Calcium Release

Waddell

Zhang

Hoeksema

et al. 2016

Biophysical Journal

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At the single-channel level, oxidation of the cardiac ryanodine receptor (RyR2) is known to activate and inhibit the channel depending on the level of oxidation. However, the mechanisms through which these changes alter the activity of RyR2 in a cellular setting are poorly understood. In this study, we determined the effect of oxidation on a common form of RyR2 regulation; store overload-induced Ca(2+) release (SOICR). We found that oxidation resulted in concentration and time-dependent changes in the activation threshold for SOICR. Low concentrations of the oxidant H2O2 resulted in a decrease in the threshold for SOICR, which led to an increase in SOICR events. However, higher concentrations of H2O2, or prolonged exposure, reversed these changes and led to an increase in the threshold for SOICR. This increase in the threshold for SOICR in most cells was to such an extent that it led to the complete inhibition of SOICR. Acute exposure to high concentrations of H2O2 led to an initial decrease and then increase in the threshold for SOICR. In the majority of cells the increased threshold could not be reversed by the application of the reducing agent dithiothreitol. Therefore, our data suggest that low levels of RyR2 oxidation increase the channel activity by decreasing the threshold for SOICR, whereas high levels of RyR2 oxidation irreversibly increase the threshold for SOICR leading to an inhibition of RyR2. Combined, this indicates that oxidation regulates RyR2 by the same mechanism as phosphorylation, methylxanthines, and mutations, via changes in the threshold for SOICR.

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“…A unifying mechanism underlying RyR2 dysfunction is store overload‐induced Ca 2+ release (SOICR) (Liu et al ., ), otherwise known as spontaneous Ca 2+ release. We and others have shown that SOICR can be triggered due to an increase in SR Ca 2+ content or due to an increase in the sensitivity of RyR2 to activation by SR Ca 2+ (Kashimura et al ., ; Zhang et al ., ; Zhang et al ., ). Pertinently, we have previously shown that the drug‐induced activation of RyR2 partially underlies the cardiotoxicity of anthracyclines, a different class of chemotherapeutic drugs (Hanna et al ., ).…”

Section: Introductionmentioning

confidence: 99%

Activation of RyR2 by class I kinase inhibitors

Chakraborty

Gonano

Munro

et al. 2019

British J Pharmacology

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Background and Purpose Kinase inhibitors are a common treatment for cancer. Class I kinase inhibitors that target the ATP‐binding pocket are particularly prevalent. Many of these compounds are cardiotoxic and can cause arrhythmias. Spontaneous release of Ca2+ via cardiac ryanodine receptors (RyR2), through a process termed store overload‐induced Ca2+ release (SOICR), is a common mechanism underlying arrhythmia. We explored whether class I kinase inhibitors could modify the activity of RyR2 and trigger SOICR to determine if this contributes to the cardiotoxic nature of these compounds. Experimental Approach The impact of class I and II kinase inhibitors on SOICR was studied in HEK293 cells and ventricular myocytes using single‐cell Ca2+ imaging. A specific effect on RyR2 was confirmed using single channel recordings. Ventricular myocytes were also used to determine if drug‐induced changes in SOICR could be reversed using anti‐SOICR agents. Key Results Class I kinase inhibitors increased the propensity of SOICR. Single channel recording showed that this was due to a specific effect on RyR2. Class II kinase inhibitors decreased the activity of RyR2 at the single channel level but had little effect on SOICR. The promotion of SOICR mediated by class I kinase inhibitors could be reversed using the anti‐SOICR agent VK‐II‐86. Conclusions and Implications Part of the cardiotoxicity of class I kinase inhibitors can be assigned to their effect on RyR2 and increase in SOICR. Compounds with anti‐SOICR activity may represent an improved treatment option for patients.

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The arrhythmogenic human HRC point mutation S96A leads to spontaneous Ca2+ release due to an impaired ability to buffer store Ca2+

Cited by 20 publications

References 46 publications

The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1

The histidine-rich calcium binding protein (HRC) promotes tumor metastasis in hepatocellular carcinoma and is upregulated by SATB1

Oxidation of RyR2 Has a Biphasic Effect on the Threshold for Store Overload-Induced Calcium Release

Activation of RyR2 by class I kinase inhibitors

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