β-Adrenergic Receptor Subtype-Specific Signaling in Cardiac Myocytes from β1 and β2 Adrenoceptor Knockout Mice
β-Adrenergic Receptor Subtype-Specific Signaling in Cardiac Myocytes from β1 and β2 Adrenoceptor Knockout Mice
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DOI：
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发表时间：
2001-09
影响因子：
3.6
通讯作者：
E. Devic;Y. Xiang;D. Gould;B. Kobilka
中科院分区：
文献类型：
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作者：
E. Devic;Y. Xiang;D. Gould;B. Kobilka
交感神经系统通过激活心肌细胞以及窦房结和传导系统中的特殊细胞上表达的β-肾上腺素能受体（AR）来调节心肌收缩力和心率。最近的临床研究表明，β-肾上腺素能受体也在心肌病发病机制中发生的心脏重塑中发挥作用。 1 和 2 肾上腺素能受体均在人和小鼠心脏中表达。我们研究了 AR 激活对野生型和受体敲除 (KO) 小鼠（1AR-KO、2AR-KO 和 12AR-KO 小鼠）新生肌细胞培养物自发收缩率的影响。刺激 2AR-KO 肌细胞中的 1AR 通过需要激活蛋白激酶 A (PKA) 的信号通路产生收缩率的最大增加。相反，刺激 1AR-KO 肌细胞中的 2AR 会对收缩率产生双相效应，最初收缩率增加，不需要 PKA，随后收缩率下降，涉及与百日咳毒素敏感 G 蛋白偶联。在 12AR-KO 肌细胞中观察到的异丙肾上腺素诱导的收缩率小幅下降可归因于 3AR。这些研究表明，所有三种 AR 亚型均在新生儿心肌细胞中表达，并且 1AR 和 2AR 与不同的信号通路偶联。
The sympathetic nervous system modulates cardiac contractility and rate by activating -adrenergic receptors (AR) expressed on cardiac myocytes and specialized cells in the sinoatrial node and the conduction system. Recent clinical studies have suggested that -adrenergic receptors also play a role in cardiac remodeling that occurs in the pathogenesis of cardiomyopathy. Both 1 and 2 adrenergic receptors are expressed in human and murine hearts. We have examined the effect of AR activation on the spontaneous contraction rate of neonatal myocyte cultures from wild-type and receptor knockout (KO) mice (1AR-KO, 2AR-KO and 12AR-KO mice). Stimulation of the 1AR in 2AR-KO myocytes produces the greatest increase in contraction rate through a signaling pathway that requires protein kinase A (PKA) activation. In contrast, stimulation of the 2AR in 1AR-KO myocytes results in a biphasic effect on contraction rate with an initial increase in rate that does not require PKA, followed by a decrease in rate that involves coupling to a pertussis toxin sensitive G protein. A small isoproterenol-induced decrease in contraction rate observed in 12AR-KO myocytes can be attributed to the 3AR. These studies show that all three AR subtypes are expressed in neonatal cardiac myocytes, and the 1AR and 2AR couple to distinct signaling pathways.