Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor-mediated cAMP signaling.
Caveolin-3 regulates compartmentation of cardiomyocyte beta2-adrenergic receptor-mediated cAMP signaling.
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DOI：
10.1016/j.yjmcc.2013.12.003
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发表时间：
2014-02
影响因子：
5
通讯作者：
Gorelik, Julia
中科院分区：
文献类型：
--
作者：
Wright, Peter T.;Nikolaev, Viacheslav O.;O'Hara, Thomas;Diakonov, Ivan;Bhargava, Anamika;Tokar, Sergiy;Schobesberger, Sophie;Shevchuk, Andrew I.;Sikkel, Markus B.;Wilkinson, Ross;Trayanova, Natalia A.;Lyon, Alexander R.;Harding, Sian E.;Gorelik, Julia
本研究旨在探讨小窝蛋白3（Cav 3）对健康和衰竭心肌细胞β2肾上腺素能受体（β2AR）定位及其cAMP信号通路的调节作用。我们在成年大鼠心室肌细胞（ARVM）中共表达野生型Cav 3或其显性负突变体（Cav 3DN）以及基于Förster共振能量转移（FRET）的cAMP传感器Epac 2-camp。用FRET和扫描离子电导显微镜局部刺激β 2 AR和测定胞浆cAMP。Cav 3过表达可增加细胞膜小窝的数量，降低β2AR-cAMP信号的强度。相反，Cav 3DN表达导致β2AR-cAMP反应增加，而不改变全细胞L型钙电流。局部刺激表达Cav 3DN的ARVM后，仅在T小管中产生β 2 AR反应。然而，正常区室化的β2AR-cAMP信号变得弥散，与心力衰竭中观察到的情况相似。最后，Cav 3在衰竭的肌细胞中的过表达导致部分β2AR重新分布回到T小管。总之，Cav 3在β2AR的定位和β2AR-cAMP信号传导至健康ARVM的T-小管的区室化中起关键作用，并且Cav 3在衰竭的肌细胞中的过表达可以部分恢复这些受体的破坏的定位。
The purpose of this study was to investigate whether caveolin-3 (Cav3) regulates localization of β2-adrenergic receptor (β2AR) and its cAMP signaling in healthy or failing cardiomyocytes. We co-expressed wildtype Cav3 or its dominant-negative mutant (Cav3DN) together with the Förster resonance energy transfer (FRET)-based cAMP sensor Epac2-camps in adult rat ventricular myocytes (ARVMs). FRET and scanning ion conductance microscopy were used to locally stimulate β2AR and to measure cytosolic cAMP. Cav3 overexpression increased the number of caveolae and decreased the magnitude of β2AR-cAMP signal. Conversely, Cav3DN expression resulted in an increased β2AR-cAMP response without altering the whole-cell L-type calcium current. Following local stimulation of Cav3DN-expressing ARVMs, β2AR response could only be generated in T-tubules. However, the normally compartmentalized β2AR-cAMP signal became diffuse, similar to the situation observed in heart failure. Finally, overexpression of Cav3 in failing myocytes led to partial β2AR redistribution back into the T-tubules. In conclusion, Cav3 plays a crucial role for the localization of β2AR and compartmentation of β2AR-cAMP signaling to the T-tubules of healthy ARVMs, and overexpression of Cav3 in failing myocytes can partially restore the disrupted localization of these receptors.
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