Sarcoplasmic reticulum Ca2+ cycling protein phosphorylation in a physiologic Ca2+ milieu unleashes a high-power, rhythmic Ca2+ clock in ventricular myocytes: relevance to arrhythmias and bio-pacemaker design.
Sarcoplasmic reticulum Ca2+ cycling protein phosphorylation in a physiologic Ca2+ milieu unleashes a high-power, rhythmic Ca2+ clock in ventricular myocytes: relevance to arrhythmias and bio-pacemaker design.
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DOI：
10.1016/j.yjmcc.2013.11.011
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发表时间：
2014-01
影响因子：
5
通讯作者：
Lakatta, Edward G.
中科院分区：
文献类型：
--
作者：
Sirenko, Syevda;Maltsev, Victor A.;Maltseva, Larissa A.;Yang, Dongmei;Lukyanenko, Yevgeniya;Vinogradova, Tatiana M.;Jones, Larry R.;Lakatta, Edward G.
关键词：
肌浆网 (SR) Ca2+ 蛋白的基础磷酸化在窦房结细胞 (SANC) 中较高，产生部分同步、自发、节律性、舒张期局部 Ca2+ 释放 (LCR)，但在心室肌细胞 (VM) 中较低，表现出罕见的舒张期、随机 SR 生成的 Ca2+ 火花。我们测试了这样的假设：在生理 Ca2+ 环境中，与增加的 Ca2+ 流入无关，SR Ca2+ 循环蛋白基础磷酸化的增加会将随机 Ca2+ 火花转化为驱动 SANC 正常自动性的周期性、高功率 Ca2+ 信号。我们测量了 SR 相关蛋白、受磷蛋白 (PLB) 和兰尼碱受体 (RyR) 的磷酸化，以及在抑制蛋白磷酸酶 (PP) 和磷酸二酯酶 (PDE) 之前和期间，或添加外源性药物之前和期间，透化的单个兔 VM 中生理 [Ca2+] 的自发局部 Ca2+ 释放特征 (LCR)。 cAMP，或在抗体 (2D12) 存在下，特异性抑制 PLB 与 SERCA-2 的结合。在没有上述扰动的情况下，VM 只能产生低功率和低幅度的随机局部 Ca2+ 释放，如共焦 Ca2+ 成像和光谱分析所评估。当通过增加 PLB 磷酸化（通过 PDE 和 PP 抑制或添加 cAMP）或通过 2D12 增加 Ca2+ 泵入 SR 的动力学时，会出现自组织的“时钟状”局部 Ca2+ 释放，在空间和时间上部分同步（Ca2+ 小波），并且这些有节奏的局部 Ca2+ 小波的集合产生周期性 高振幅 Ca2+ 信号。因此，Ca2+时钟不是起搏细胞特有的，但当SR Ca2+循环增加并且自发的局部Ca2+释放变得部分同步时，也可以在VM中释放。然而，VM 生理 Ca2+ 环境中出现的这种释放的 Ca2+ 时钟有两个方面：它可以引发室性心律失常；或者如果加以利用，可以成为新型生物起搏器设计的一个重要特征。
Basal phosphorylation of sarcoplasmic reticulum (SR) Ca2+ proteins is high in sinoatrial nodal cells (SANC), which generate partially synchronized, spontaneous, rhythmic, diastolic local Ca2+ releases (LCRs), but low in ventricular myocytes (VM), which exhibit rare diastolic, stochastic SR-generated Ca2+ sparks. We tested the hypothesis that in a physiologic Ca2+ milieu, and independent of increased Ca2+ influx, an increase in basal phosphorylation of SR Ca2+ cycling proteins will convert stochastic Ca2+ sparks into periodic, high-power Ca2+ signals of the type that drives SANC normal automaticity. We measured phosphorylation of SR-associated proteins, phospholamban (PLB) and ryanodine receptors (RyR), and spontaneous local Ca2+ release characteristics (LCR) in permeabilized single, rabbit VM in physiologic [Ca2+], prior to and during inhibition of protein phosphatase (PP) and phosphodiesterase (PDE), or addition of exogenous cAMP, or in the presence of an antibody (2D12), that specifically inhibits binding of the PLB to SERCA-2. In the absence of the aforementioned perturbations, VM could only generate stochastic local Ca2+ releases of low power and low amplitude, as assessed by confocal Ca2+ imaging and spectral analysis. When the kinetics of Ca2+ pumping into the SR were increased by an increase in PLB phosphorylation (via PDE and PP inhibition or addition of cAMP) or by 2D12, self-organized, “clock-like” local Ca2+ releases, partially synchronized in space and time (Ca2+ wavelets), emerged, and the ensemble of these rhythmic local Ca2+ wavelets generated a periodic high-amplitude Ca2+ signal. Thus, a Ca2+ clock is not specific to pacemaker cells, but can also be unleashed in VM when SR Ca2+ cycling increases and spontaneous local Ca2+ release becomes partially synchronized. This unleashed Ca2+ clock that emerges in a physiological Ca2+ milieu in VM has two faces, however: it can provoke ventricular arrhythmias; or if harnessed, can be an important feature of novel bio-pacemaker designs.
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影响因子：
46.9
作者：
通讯作者：
--
影响因子：
5
作者：
Maltsev VA;Lakatta EG
通讯作者：
Lakatta EG
影响因子：
64.5
作者：
Marx, SO;Reiken, S;Marks, AR
通讯作者：
Marks, AR
影响因子：
20.1
作者：
Lyashkov, Alexey E.;Juhaszova, Magdalena;Lakatta, Edward G.
通讯作者：
Lakatta, Edward G.
影响因子：
2.9
作者：
Mahaney, JE;Albers, RW;Froehlich, JP
通讯作者：
Froehlich, JP