Endogenous RGS proteins modulate SA and AV nodal functions in isolated heart: implications for sick sinus syndrome and AV block
Endogenous RGS proteins modulate SA and AV nodal functions in isolated heart: implications for sick sinus syndrome and AV block
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DOI：
10.1152/ajpheart.01391.2006
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发表时间：
2007-05-01
影响因子：
4.8
通讯作者：
Neubig, Richard R.
中科院分区：
文献类型：
--
作者：
Fu, Ying;Huang, Xinyan;Neubig, Richard R.
G蛋白偶联受体在调节心脏自律性中起关键作用。它们的功能由G蛋白信号传导调节因子（RGS）蛋白控制，所述RGS蛋白充当Ga亚基的GTP酶激活蛋白以抑制G α（i）和G α（q）信号传导。使用基因敲入小鼠，其中G α（i2）-RGS结合和负调节被基因组G α（i2）G184 S（GS）点突变破坏，我们最近（Fu Y，Huang X，Zhong H，Mortensen RM，D 'Alfred LG，Neubig RR. Circ Res 98：659 - 666，2006）显示内源性RGS蛋白抑制毒蕈碱受体介导的心动过缓。为了确定这是否是由于心脏起搏器的直接调节或中枢神经系统或血管反应的改变，我们检查了离体灌注心脏。异丙肾上腺素刺激的心跳率的杂合子（+/GS）和纯合子（GS/GS）的心脏显着更敏感的抑制卡巴胆碱比野生型（+/+）。在不存在异丙肾上腺素的情况下观察到更大的作用;与+/+相比，毒蕈碱介导的心动过缓的效力在GS/GS中增强了5倍，在+/GS心脏中增强了2倍。腺苷受体介导的心动过缓不受影响。除了对窦房结的影响外，+/GS和GS/GS心脏显示卡巴胆碱诱导的三度房室（AV）阻滞显著增加。心房起搏研究表明，与+/+相比，GS/GS心脏的PR间期和AV有效不应期延长。因此，内源性RGS蛋白对G α（i2）的抑制作用的丧失增强了毒蕈碱对心脏自律性和传导的抑制。G α（i2）G184 S小鼠中严重的卡巴胆碱诱导的窦性心动过缓表明G α（i2）或RGS蛋白的改变在病窦综合征和病理性房室传导阻滞中可能起作用。
G protein-coupled receptors play a pivotal role in regulating cardiac automaticity. Their function is controlled by regulator of G protein signaling (RGS) proteins acting as GTPase-activating proteins for Ga subunits to suppress G alpha(i) and G alpha(q) signaling. Using knock-in mice in which G alpha(i2)-RGS binding and negative regulation are disrupted by a genomic G alpha(i2)G184S (GS) point mutation, we recently (Fu Y, Huang X, Zhong H, Mortensen RM, D'Alecy LG, Neubig RR. Circ Res 98: 659 - 666, 2006) showed that endogenous RGS proteins suppress muscarinic receptor-mediated bradycardia. To determine whether this was due to direct regulation of cardiac pacemakers or to alterations in the central nervous system or vascular responses, we examined isolated, perfused hearts. Isoproterenol-stimulated beating rates of heterozygote (+/GS) and homozygote (GS/GS) hearts were significantly more sensitive to inhibition by carbachol than were those of wild type (+/+). Even greater effects were seen in the absence of isoproterenol; the potency of muscarinic-mediated bradycardia was enhanced fivefold in GS/GS and twofold in +/GS hearts compared with +/+. A(1)-adenosine receptor-mediated bradycardia was unaffected. In addition to effects on the sinoatrial node, +/GS and GS/GS hearts show significantly increased carbachol-induced third-degree atrioventricular (AV) block. Atrial pacing studies demonstrated an increased PR interval and AV effective refractory period in GS/GS hearts compared with +/+. Thus loss of the inhibitory action of endogenous RGS proteins on G alpha(i2) potentiates muscarinic inhibition of cardiac automaticity and conduction. The severe carbachol-induced sinus bradycardia in G alpha(i2)G184S mice suggests a possible role for alterations of G alpha(i2) or RGS proteins in sick sinus syndrome and pathological AV block.