Modified sympathetic nerve system activity with overexpression of the voltage-dependent calcium channel beta3 subunit.
Modified sympathetic nerve system activity with overexpression of the voltage-dependent calcium channel beta3 subunit.
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DOI：
10.1074/jbc.m802319200
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发表时间：
2008-09-05
期刊：
影响因子：
--
通讯作者：
Iijima, Toshihiko
中科院分区：
文献类型：
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作者：
Murakami, Manabu;Ohba, Takayoshi;Iijima, Toshihiko
n型电压依赖性钙通道（VDCCs）在交感神经末梢钙进入和触发神经递质去甲肾上腺素的释放中起决定性作用。这些通道的附属beta3亚基优先与成孔CaV2.2亚基形成n型通道。为了研究其在交感神经调节中的作用，我们建立了过表达beta3的转基因（beta3-Tg）小鼠系。在这些小鼠中，我们用Langendorff仪器分析了心血管功能，如心电图、血压、超声心动图和左心室等容收缩。此外，我们将心脏功能与β - 3缺失和CaV2.2 （alpha1B）缺失小鼠进行比较。β 3- tg小鼠显示β 3亚基的表达增加，导致颈上神经节（SCG）神经元中CaV2.2的量增加。β 3- tg小鼠心率增加，对心电图、血压和超声心动图中n型通道特异性阻滞剂的敏感性增强。与此相反，β 3- tg小鼠心房对异丙肾上腺素表现出正常的收缩性。此外，它们的心肌细胞显示正常的钙通道电流，表明通过vdcs的钙流入没有改变。Langendorff心脏灌注分析显示，β - t3 - tg小鼠对电场刺激的敏感性增强，而β - t3 -null和Cav2.2-null小鼠的反应性降低。β 3- tg小鼠血浆肾上腺素和去甲肾上腺素水平在基础状态下显著升高，表明交感神经张力增强。β 3- tg小鼠SCG神经元电生理分析显示钙通道电流增加，特别是N型和l型电流。这些结果确定了β a3亚基在SCG n型通道群中的决定性作用，并在交感神经调节中起主要作用。
N-type voltage-dependent calcium channels (VDCCs) play determining roles in calcium entry at sympathetic nerve terminals and trigger the release of the neurotransmitter norepinephrine. The accessory beta3 subunit of these channels preferentially forms N-type channels with a pore-forming CaV2.2 subunit. To examine its role in sympathetic nerve regulation, we established a beta3-overexpressing transgenic (beta3-Tg) mouse line. In these mice, we analyzed cardiovascular functions such as electrocardiography, blood pressure, echocardiography, and isovolumic contraction of the left ventricle with a Langendorff apparatus. Furthermore, we compared the cardiac function with that of beta3-null and CaV2.2 (alpha1B)-null mice. The beta3-Tg mice showed increased expression of the beta3 subunit, resulting in increased amounts of CaV2.2 in supracervical ganglion (SCG) neurons. The beta3-Tg mice had increased heart rate and enhanced sensitivity to N-type channel-specific blockers in electrocardiography, blood pressure, and echocardiography. In contrast, cardiac atria of the beta3-Tg mice revealed normal contractility to isoproterenol. Furthermore, their cardiac myocytes showed normal calcium channel currents, indicating unchanged calcium influx through VDCCs. Langendorff heart perfusion analysis revealed enhanced sensitivity to electric field stimulation in the beta3-Tg mice, whereas beta3-null and Cav2.2-null showed decreased responsiveness. The plasma epinephrine and norepinephrine levels in the beta3-Tg mice were significantly increased in the basal state, indicating enhanced sympathetic tone. Electrophysiological analysis in SCG neurons of beta3-Tg mice revealed increased calcium channel currents, especially N- and L-type currents. These results identify a determining role for the beta3 subunit in the N-type channel population in SCG and a major role in sympathetic nerve regulation.