Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8474710 | Journal of Molecular and Cellular Cardiology | 2014 | 10 Pages |
Abstract
The Ser96Ala (S96A) mutation within the histidine rich Ca2Â + binding protein (HRC) has recently been linked to cardiac arrhythmias in idiopathic dilated cardiomyopathy patients, potentially attributable to an increase in spontaneous Ca2Â + release events. However, the molecular mechanism connecting the S96A mutation of HRC to increased Ca2Â + release events remains unclear. Previous findings by our group indicate that these spontaneous Ca2Â + release events may be linked to store overload induced Ca2Â + release (SOICR) via the cardiac ryanodine receptor (RyR2). Therefore, in the present study we sought to determine whether HRC wild type (HRC WT) and S96A mutant (HRC S96A) expression has a direct effect on SOICR. Using both cytosolic and intra-Ca2Â + store measurements in human embryonic kidney cells expressing RyR2, we found that HRC WT significantly inhibited the propensity for SOICR by buffering store free Ca2Â + and inhibiting store Ca2Â + uptake. In contrast, HRC S96A exhibited a markedly suppressed inhibitory effect on SOICR, which was attributed to an impaired ability to buffer store Ca2Â + and reduce store Ca2Â + uptake. In addition to impairing the ability of HRC to regulate bulk store Ca2Â +, a proximity ligation assay demonstrated that the S96A mutation also disrupts the Ca2Â + microdomain around the RyR2, as it alters the Ca2Â + dependent association of RyR2 and HRC. Importantly, in contrast to previous reports, the absence of triadin in our experimental model illustrates that the S96A mutation in HRC can alter the propensity for SOICR without any interaction with triadin. Collectively, our results demonstrate that the human HRC mutation S96A leads to an increase in spontaneous Ca2Â + release and ultimately arrhythmias by disrupting the regulation of intra-store free Ca2Â +. This is primarily due to an impaired ability to act as an effective bulk and local microdomain store Ca2Â + buffer.
Keywords
Related Topics
Life Sciences
Biochemistry, Genetics and Molecular Biology
Cell Biology
Authors
Joe Z. Zhang, Janet C. McLay, Peter P. Jones,