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Deletion of cardiac polycystin 2/PC2 results in increased SR calcium release and blunted adrenergic reserve.
American Journal of Physiology-Heart and Circulatory Physiology ( IF 4.1 ) Pub Date : 2020-09-18 , DOI: 10.1152/ajpheart.00302.2020
Elisabeth DiNello 1, 2 , Elisa Bovo 1, 2 , Paula Thuo 1, 2 , Thomas G Martin 3 , Jonathan A Kirk 1, 2 , Aleksey V Zima 1, 2 , Quan Cao 1, 2 , Ivana Y Kuo 1, 2, 4
Affiliation  

Transient receptor potential proteins (TRPs) act as non-selective cation channels. Of the TRP channels, PC2- also known as polycystin 2- is localized to the sarcoplasmic reticulum (SR), however its contribution to calcium induced calcium release (CICR) and overall cardiac function in the heart is poorly understood. The goal of this study was to characterize the effect of cardiac specific PC2 deletion in adult cardiomyocytes, and in response to chronic β-adrenergic challenge. We used a temporally inducible model to specifically delete PC2 from cardiomyocytes (Pkd2 KO), and characterized calcium and contractile dynamics in single cells. We found enhanced intracellular calcium release after Pkd2 KO, and near super-resolution microscopy analysis suggested this was due to close localization of PC2 to the ryanodine receptor. At the organ level, speckle-tracking echocardiographical analysis showed increased dyssynchrony in the Pkd2 KO mice. In response to chronic adrenergic stimulus, cardiomyocytes from the Pkd2 KO had no reserve β-adrenergic calcium responses, and significantly attenuated wall motion in the whole heart. Biochemically, without adrenergic stimulus, there was an overall increase in PKA phosphorylated targets in the Pkd2 KO mouse, which decreased following chronic adrenergic stimulus. Taken together, our results suggest that cardiac specific PC2 limits SR calcium release by affecting the PKA phosphorylation status of the ryanodine receptor, and the effects of PC2 loss are exacerbated upon adrenergic challenge.

中文翻译:

心脏多囊蛋白 2/PC2 的缺失导致 SR 钙释放增加和肾上腺素能储备减弱。

瞬时受体电位蛋白 (TRP) 充当非选择性阳离子通道。在 TRP 通道中,PC2-也称为多囊蛋白 2-定位于肌浆网 (SR),但其对钙诱导钙释放 (CICR) 和心脏整体心脏功能的贡献知之甚少。本研究的目的是表征心脏特异性 PC2 缺失对成年心肌细胞的影响,以及对慢性 β-肾上腺素能挑战的反应。我们使用时间诱导模型从心肌细胞 (Pkd2 KO) 中特异性删除 PC2,并表征单细胞中的钙和收缩动力学。我们发现 Pkd2 KO 后细胞内钙释放增强,近超分辨率显微镜分析表明这是由于 PC2 与兰尼碱受体的紧密定位。在器官层面,斑点跟踪超声心动图分析显示 Pkd2 KO 小鼠的不同步性增加。响应慢性肾上腺素能刺激,来自 Pkd2 KO 的心肌细胞没有储备 β-肾上腺素能钙反应,并且显着减弱了整个心脏的壁运动。在生化方面,在没有肾上腺素能刺激的情况下,Pkd2 KO 小鼠中 PKA 磷酸化靶标的总体增加,在慢性肾上腺素能刺激后下降。总之,我们的结果表明,心脏特异性 PC2 通过影响兰尼碱受体的 PKA 磷酸化状态来限制 SR 钙的释放,并且在肾上腺素能激发时会加剧 PC2 丢失的影响。来自 Pkd2 KO 的心肌细胞没有储备 β-肾上腺素能钙反应,并且显着减弱了整个心脏的壁运动。生化上,在没有肾上腺素能刺激的情况下,Pkd2 KO 小鼠中 PKA 磷酸化靶标的总体增加,在慢性肾上腺素能刺激后下降。总之,我们的结果表明,心脏特异性 PC2 通过影响兰尼碱受体的 PKA 磷酸化状态来限制 SR 钙的释放,并且在肾上腺素能激发时会加剧 PC2 丢失的影响。来自 Pkd2 KO 的心肌细胞没有储备 β-肾上腺素能钙反应,并且显着减弱了整个心脏的壁运动。生化上,在没有肾上腺素能刺激的情况下,Pkd2 KO 小鼠中 PKA 磷酸化靶标的总体增加,在慢性肾上腺素能刺激后下降。总之,我们的结果表明,心脏特异性 PC2 通过影响兰尼碱受体的 PKA 磷酸化状态来限制 SR 钙的释放,并且在肾上腺素能激发时会加剧 PC2 丢失的影响。
更新日期:2020-09-20
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