The in vivo regulation of heart rate in the murine sinoatrial node by stimulatory and inhibitory heterotrimeric G proteins
The in vivo regulation of heart rate in the murine sinoatrial node by stimulatory and inhibitory heterotrimeric G proteins
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DOI：
10.1152/ajpregu.00037.2013
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发表时间：
2013-08-01
影响因子：
2.8
通讯作者：
Tinker, Andrew
中科院分区：
文献类型：
--
作者：
Sebastian, Sonia;Ang, Richard;Tinker, Andrew
心率的相互生理调节由作用于窦房（SA）结的交感神经和副交感神经系统控制。然而，很少有直接在体内的工作检查的作用，刺激和抑制G蛋白信号在SA节点。因此，我们设计了一项研究，以检查刺激性（G α s）和抑制性G蛋白（G α i2）在小鼠SA结中的体内心率调节中的作用。我们使用cre-loxP技术研究了传导系统中G α s和G α i2条件性缺失的小鼠。我们将cre重组酶表达由他莫昔芬诱导的传导系统特异性构建体驱动的小鼠与“G α s floxed”和“G α i2 floxed”小鼠杂交。我们研究了心率反应的成年小鼠与同窝对照组相比，使用无线电遥测之前和之后的他莫昔芬管理。条件性缺失G α s和G α i2的小鼠昼夜变化丧失，白天分别为心动过缓或心动过速。在有条件缺失G α s的小鼠中，在心率变异性的功率谱分析中，存在低频功率的选择性损失，而缺失G α i2，则存在高频功率的损失。没有病理性心律失常的证据。异丙肾上腺素对心率的药理学调节在G α s小鼠中受损，但毒蕈碱激动剂仍然能够减慢G α i2小鼠的心率。我们的结论是，G α s-和G α i2-介导的信号在窦房结是重要的心率通过自主神经系统的相互调节。
Reciprocal physiological modulation of heart rate is controlled by the sympathetic and parasympathetic systems acting on the sinoatrial (SA) node. However, there is little direct in vivo work examining the role of stimulatory and inhibitory G protein signaling in the SA node. Thus, we designed a study to examine the role of the stimulatory (G alpha s) and inhibitory G protein (G alpha i2) in in vivo heart rate regulation in the SA node in the mouse. We studied mice with conditional deletion of G alpha s and G alpha i2 in the conduction system using cre-loxP technology. We crossed mice in which cre recombinase expression was driven by a tamoxifen-inducible conduction system-specific construct with "G alpha s floxed" and "G alpha i2 floxed" mice. We studied the heart rate responses of adult mice compared with littermate controls by using radiotelemetry before and after administration of tamoxifen. The mice with conditional deletion of G alpha s and G alpha i2 had a loss of diurnal variation and were bradycardic or tachycardic, respectively, in the daytime. In mice with conditional deletion of G alpha s, there was a selective loss of low-frequency power, while with deletion of G alpha i2, there was a loss of high-frequency power in power spectral analysis of heart rate variability. There was no evidence of pathological arrhythmia. Pharmacological modulation of heart rate by isoprenaline was impaired in the G alpha s mice, but a muscarinic agonist was still able to slow the heart rate in G alpha i2 mice. We conclude that G alpha s- and G alpha i2-mediated signaling in the sinoatrial node is important in the reciprocal regulation of heart rate through the autonomic nervous system.