Altered airway and cardiac responses in mice lacking G protein-coupled receptor kinase 3
Altered airway and cardiac responses in mice lacking G protein-coupled receptor kinase 3
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DOI：
10.1152/ajpregu.1999.276.4.r1214
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发表时间：
1999-04-01
影响因子：
2.8
通讯作者：
Fisher, JT
中科院分区：
文献类型：
--
作者：
Walker, JKL;Peppel, K;Fisher, JT
气道平滑肌的收缩和舒张部分由G蛋白偶联受体（GPCR）介导，并且这些受体的功能障碍与哮喘有关。GPCR的磷酸化，尝试G蛋白偶联受体激酶（GRK），是参与抑制GPCR信号传导的重要机制。为了确定这种机制是否可能在气道平滑肌生理学中发挥作用，我们在缺乏一个GRK 2拷贝的遗传改变小鼠（GRK 2 +/-）、纯合子GRK 3敲除小鼠（GRK 3-/-）和野生型同窝小鼠中检查了静脉给予胆碱能激动剂乙酰甲胆碱（MCh）的气道压力时间指数和心率（HR）反应。(GRK2-/-小鼠在子宫内死亡。）与野生型和GRK 2 +/-小鼠相比，GRK 3-/-小鼠对100和250 μ g/kg剂量的MCh的气道反应显着增强。GRK 3-/-小鼠还显示出气道平滑肌对MCh反应的敏感性增强。此外，GRK 3-/-小鼠显示出从MCH诱导的心动过缓中恢复的改变的HR。虽然直接刺激心脏毒蕈碱受体测量为迷走神经刺激诱导的心动过缓是相似的GRK 3-/-和野生型小鼠，与硝普钠诱导的低血压相关的HR的压力反射增加显着大于GRK 3-/-比野生型小鼠。因此，这些数据表明，在小鼠中，GRK 3可能参与调节气道平滑肌的胆碱能反应和调节压力感受器反射的变时成分。
Contraction and relaxation of airway smooth muscles is mediated, in part, by G protein-coupled receptors (GPCRs) and dysfunction of these receptors has been implicated in asthma. Phosphorylation of GPCRs, try G protein-coupled receptor kinase (GRK), is an important mechanism involved in the dampening of GPCR signaling. To determine whether this mechanism might play a role in airway smooth muscle physiology, we examined the airway pressure time index and heart rate (HR) responses to intravenous administration of the cholinergic agonist methacholine (MCh) in genetically altered mice lacking one copy of GRK2 (GRK2 +/-), homozygous GRK3 knockout (GRK3 -/-), and wild-type littermates. (GRK2 -/- mice die in utero.) GRK3 -/- mice demonstrated a significant enhancement in the airway response to 100 and 250 mu g/kg doses of MCh compared with wild-type and GRK2 +/- mice. GRK3 -/- mice also displayed an enhanced sensitivity of the airway smooth muscle response to MCh. In addition, GRK3 -/- mice displayed an altered HR recovery from MCh-induced bradycardia. Although direct stimulation of cardiac muscarinic receptors measured as vagal stimulation-induced bradycardia was similar in GRK3 -/- and wild-type mice, the baroreflex increase in HR associated with sodium nitroprusside-induced hypotension was significantly greater in GRK3 -/- than wild-type mice. Therefore, these data demonstrate that in the mouse, GRK3 may be involved in modulating the cholinergic response of airway smooth muscle and in regulating the chronotropic component of the baroreceptor reflex.