G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation.
G protein-coupled receptor kinase 5 regulates airway responses induced by muscarinic receptor activation.
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DOI：
10.1152/ajplung.00255.2003
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发表时间：
2004-02
期刊：
影响因子：
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通讯作者：
J. K. Walker;R. Gainetdinov;D. S. Feldman;P. McFawn;M. Caron;R. Lefkowitz;R. T. Premont;J. Fisher
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文献类型：
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作者：
J. K. Walker;R. Gainetdinov;D. S. Feldman;P. McFawn;M. Caron;R. Lefkowitz;R. T. Premont;J. Fisher
G蛋白偶联受体（gpcr）将细胞外信号转导为细胞内事件。面对持续的激动剂刺激，gpcr的反应性减弱，或脱敏，是确保生理稳态的必要事件。GPCR激酶（GRKs）是GPCR脱敏的重要调控因子。GRK5是GRK家族的一员，可使小鼠中枢M(2)毒蕈碱受体脱敏。我们质疑GRK5是否也可能是心肺系统外周毒蕈碱受体反应性的重要调节因子。具体来说，我们想确定GRK5在调节毒蕈碱受体介导的气道平滑肌张力控制或调节胆碱能诱导的心动过缓中的作用。在GRK5基因靶向缺失的小鼠（GRK5(-/-)）和野生型（WT）对照小鼠中测量了气管压力、心率和气管平滑肌张力。体内和体外实验结果表明，GRK5（-/-）和WT小鼠对毒蕈碱受体激动剂的气道收缩反应没有差异。然而，在GRK5（-/-）小鼠中，双侧迷走神经刺激的松弛成分和β(2)-肾上腺素能受体激活引起的气道平滑肌松弛减少。这些数据表明，M(2)毒蕈碱受体介导的气道平滑肌舒张拮抗受GRK5调控，因此在GRK5（-/-）小鼠中是过量的。此外，本研究表明GRK5以组织和受体特异性的方式调节肺反应，但不调节外周心脏毒蕈碱受体。GRK5对气道反应的调节可能对哮喘或慢性阻塞性肺疾病等阻塞性气道疾病有影响。
G protein-coupled receptors (GPCRs) transduce extracellular signals into intracellular events. The waning responsiveness of GPCRs in the face of persistent agonist stimulation, or desensitization, is a necessary event that ensures physiological homeostasis. GPCR kinases (GRKs) are important regulators of GPCR desensitization. GRK5, one member of the GRK family, desensitizes central M(2) muscarinic receptors in mice. We questioned whether GRK5 might also be an important regulator of peripheral muscarinic receptor responsiveness in the cardiopulmonary system. Specifically, we wanted to determine the role of GRK5 in regulating muscarinic receptor-mediated control of airway smooth muscle tone or regulation of cholinergic-induced bradycardia. Tracheal pressure, heart rate, and tracheal smooth muscle tension were measured in mice having a targeted deletion of the GRK5 gene (GRK5(-/-)) and littermate wild-type (WT) control mice. Both in vivo and in vitro results showed that the airway contractile response to a muscarinic receptor agonist was not different between GRK5(-/-) and WT mice. However, the relaxation component of bilateral vagal stimulation and the airway smooth muscle relaxation resulting from beta(2)-adrenergic receptor activation were diminished in GRK5(-/-) mice. These data suggest that M(2) muscarinic receptor-mediated opposition of airway smooth muscle relaxation is regulated by GRK5 and is, therefore, excessive in GRK5(-/-) mice. In addition, this study shows that GRK5 regulates pulmonary responses in a tissue- and receptor-specific manner but does not regulate peripheral cardiac muscarinic receptors. GRK5 regulation of airway responses may have implications in obstructive airway diseases such as asthma or chronic obstructive pulmonary disease.