A calcium-induced calcium release mechanism mediated by calsequestrin
A calcium-induced calcium release mechanism mediated by calsequestrin
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DOI：
10.1016/j.jtbi.2008.04.027
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发表时间：
2008-08-21
影响因子：
2
通讯作者：
Keener, James P.
中科院分区：
文献类型：
--
作者：
Lee, Young-Seon;Keener, James P.
钙离子诱导的钙离子释放（CICR）被广泛认为是心肌细胞电兴奋和机械收缩的主要机制。CICR的机制主要是基于细胞内Ca 2+与RyR的结合并诱导Ca 2+从SR释放。然而，最近的实验表明，SR内腔Ca 2+也可能参与调节RyR门控通过钙螯合蛋白（CSQ），SR内腔Ca 2+缓冲。我们研究如何SR钙释放通过RyR是由Ca 2+和钙螯合蛋白（CSQ）调节。首先，RyR动力学的数学模型是根据实验证据。我们假设RyR有三个结合位点，两个胞质位点用于Ca 2+激活和失活，一个SR内腔位点用于CSQ结合。开放概率（P）的RyR是通过模拟控制胞质和SR内腔Ca ~（2+）。随着SR腔内C2+的增加，峰值和稳态P均有效地增加。其次，我们将RyR模型纳入CICR模型，该模型具有二元空间和连接SR（jSR）。在低jSR Ca 2+负荷下，CSQ更可能与RyR结合并抑制jSR Ca 2+释放，而在高SR负荷下，CSQ更可能与RyR分离，从而增加jSR Ca 2+释放。此外，该CICR模型产生分数jSR Ca 2+释放和jSR负荷之间的非线性关系。这些发现与脂质双层和心肌细胞的实验观察一致。(C)2008爱思唯尔有限公司版权所有。
Calcium (Ca2+)-induced Ca2+ release (CICR) is widely accepted as the principal mechanism linking electrical excitation and mechanical contraction in cardiac cells. The CICR mechanism has been understood mainly based on binding of cytosolic Ca2+ with ryanodine receptors (RyRs) and inducing Ca2+ release from the sarroplasmic reticulum (SR). However, recent experiments suggest that SR lumenal Ca2+ may also participate in regulating RyR gating through calsequestrin (CSQ), the SR lumenal Ca2+ buffer. We investigate how SR Ca2+ release via RyR is regulated by Ca2+ and calsequestrin (CSQ). First, a mathematical model of RyR kinetics is derived based on experimental evidence. We assume that the RyR has three binding sites, two cytosolic sites for Ca2+ activation and inactivation, and one SR lumenal site for CSQ binding. The open probability (P.) of the RyR is found by simulation under controlled cytosolic and SR lumenal Ca2+. Both peak and steady-state P, effectively increase as SR lumenal C2+ increases. Second, we incorporate the RyR model into a CICR model that has both a diadic space and the junctional SR (jSR). At low jSR Ca2+ loads, CSQs are more likely to bind with the RyR and act to inhibit jSR Ca2+ release, while at high SR loads CSQs are more likely to detach from the RyR, thereby increasing jSR Ca2+ release. Furthermore, this CICR model produces a nonlinear relationship between fractional jSR Ca2+ release and jSR load. These findings agree with experimental observations in lipid bilayers and cardiac myocytes. (C) 2008 Elsevier Ltd. All rights reserved.