Deletion of cardiac polycystin 2/PC2 results in increased SR calcium release and blunted adrenergic reserve. Journal Article

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Authors: DiNello, E; Bovo, E; Thuo, P; Martin, TG; Kirk, JA; Zima, AV; Cao, Q; Kuo, IY
Article Title: Deletion of cardiac polycystin 2/PC2 results in increased SR calcium release and blunted adrenergic reserve.
Abstract: 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 ß-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 ß-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.
Journal Title: American journal of physiology. Heart and circulatory physiology
Publisher: Unknown  
Date Published: 2020