In the RyR2R4496C Mouse Model of CPVT, &bgr;-Adrenergic Stimulation Induces Ca Waves by Increasing SR Ca Content and Not by Decreasing the Threshold for Ca Waves
In the RyR2R4496C Mouse Model of CPVT, &bgr;-Adrenergic Stimulation Induces Ca Waves by Increasing SR Ca Content and Not by Decreasing the Threshold for Ca Waves
复制标题
在 CPVT 的 RyR2R4496C 小鼠模型中，
作者：
T. Kashimura;S. Briston;A. Trafford;C. Napolitano;S. Priori;D. Eisner;L. Venetucci
原理：兰尼碱受体（RyR）突变可引起儿茶酚胺能多形性室性心动过速（CPVT）。这些突变易导致肾上腺素能刺激时产生钙波和延迟后去极化。当肌浆网（SR）Ca含量升高超过阈值或阈值降低时，出现Ca波。这些发生在表达CPVT突变的心肌细胞中尚不清楚。目的：探讨正常人和CPVT患者的阈SR Ca含量是否存在差异，以及这种差异与肾上腺素能刺激时SR Ca含量的关系。方法和结果：对来自CPVT RyR 2 R4496 C +/−小鼠模型和野生型（WT）对照的心室肌细胞进行电压钳位;测量舒张期SR Ca含量并与Ca波阈值进行比较。结果表明：(1)在1 mmol/L [Ca ~（2+）]o ~（2+）时，用异丙肾上腺素（1 mol/L）刺激肾上腺素能，仅在R4496 C产生Ca波。(2)R4496 C组SR Ca含量和Ca波阈值均低于WT组。(3)- 肾上腺素能刺激在R4496 C和WT中增加SR Ca含量的量相似。(4)- 肾上腺素能刺激增加Ca波的阈值。(5)在肾上腺素能刺激R4496 C，而不是WT，SR钙的增加足以达到阈值，并产生钙波。结论：R4496 C CPVT模型中，RyR是泄漏的，这降低了SR Ca含量和波的阈值。&bgr;- 肾上腺素能刺激通过增加SR Ca含量而不是通过降低阈值产生Ca波。
Rationale: Mutations of the ryanodine receptor (RyR) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). These mutations predispose to the generation of Ca waves and delayed afterdepolarizations during adrenergic stimulation. Ca waves occur when either sarcoplasmic reticulum (SR) Ca content is elevated above a threshold or the threshold is decreased. Which of these occurs in cardiac myocytes expressing CPVT mutations is unknown. Objective: We tested whether the threshold SR Ca content is different between control and CPVT and how it relates to SR Ca content during &bgr;-adrenergic stimulation. Methods and Results: Ventricular myocytes from the RyR2 R4496C+/− mouse model of CPVT and wild-type (WT) controls were voltage-clamped; diastolic SR Ca content was measured and compared with the Ca wave threshold. The results showed the following. (1) In 1 mmol/L [Ca2+]o, &bgr;-adrenergic stimulation with isoproterenol (1&mgr;mol/L) caused Ca waves only in R4496C. (2) SR Ca content and Ca wave threshold in R4496C were lower than those in WT. (3) &bgr;-Adrenergic stimulation increased SR Ca content by a similar amount in both R4496C and WT. (4) &bgr;-Adrenergic stimulation increased the threshold for Ca waves. (5) During &bgr;-adrenergic stimulation in R4496C, but not WT, the increase of SR Ca was sufficient to reach threshold and produce Ca waves. Conclusions: In the R4496C CPVT model, the RyR is leaky, and this lowers both SR Ca content and the threshold for waves. &bgr;-Adrenergic stimulation produces Ca waves by increasing SR Ca content and not by lowering threshold.
DOI：
10.1152/ajpheart.00748.2003
发表时间：
2004-04-01
影响因子：
4.8
作者：
Cordeiro, JM;Greene, L;Antzelevitch, C
通讯作者：
Antzelevitch, C
DOI：
10.1073/pnas.0402388101
发表时间：
2004-08-31
影响因子：
11.1
作者：
Jiang, DW;Xiao, BL;Chen, SRW
通讯作者：
Chen, SRW