Transcriptional response to persistent β2-adrenergic receptor signaling reveals regulation of phospholamban, which alters airway contractility
Transcriptional response to persistent β2-adrenergic receptor signaling reveals regulation of phospholamban, which alters airway contractility
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DOI：
10.1152/physiolgenomics.00044.2006
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发表时间：
2006-10-11
影响因子：
4.6
通讯作者：
Liggett, Stephen B.
中科院分区：
文献类型：
--
作者：
McGraw, Dennis W.;Fogel, Kevin M.;Liggett, Stephen B.
对持续性β 2-肾上腺素能受体信号传导的转录反应揭示了受磷蛋白的调节，其改变气道收缩性。Physiol Genomics 27：171-177，2006.首次发表于2006年7月18日; doi：10.1152/physiolgenomics。00044.2006.-β（2）-肾上腺素能受体（β（2）AR）在气道平滑肌细胞上表达，并在被β-激动剂激活时起到松弛气道的作用。这些药物用于治疗哮喘，但与不良后果有关。为了确定持续的β 2 AR激活对基因表达的影响，对来自野生型（WT）和过度表达β 2 AR的转基因小鼠的培养气道平滑肌细胞进行DNA微阵列分析; 319个基因增加，164个基因减少。在来自22个Gene Ontology Slim类别的基因中观察到差异表达，包括与离子转运和钙离子结合相关的基因。在β 2 AR过表达细胞中观察到受磷蛋白（PLN）降低60%（P = 0.008），这是一种位于心肌细胞信号节点的细胞内Ca 2+浓度（[Ca 2 +]（i））处理蛋白，并在蛋白质水平上得到证实。为了分离PLN减少对气道平滑肌的生理影响，研究了WT和PLN-/-小鼠的气道收缩和舒张反应。PLN-/-小鼠对乙酰甲胆碱的收缩反应显著降低。相比之下，β-激动剂的支气管扩张作用在WT和PLN-/-小鼠之间没有差异。这些结果揭示了β-激动剂PLN下调的非预期治疗效果，其作用是降低气道高反应性。因此，抑制PLN的药剂可与β-激动剂的支气管扩张作用协同作用。许多与[Ca 2 +]（i）相关的其他基因也受到β（2）AR活性的差异调节，其中一些可能起到对抗或增强慢性β激动剂疗效的作用。这些基因或途径也可能代表治疗哮喘和相关阻塞性肺病的额外靶点。
Transcriptional response to persistent beta(2)-adrenergic receptor signaling reveals regulation of phospholamban, which alters airway contractility. Physiol Genomics 27: 171-177, 2006. First published July 18, 2006; doi:10.1152/physiolgenomics. 00044.2006.-beta(2)-Adrenergic receptors (beta(2)AR) are expressed on airway smooth muscle cells and act to relax the airway on activation by beta-agonists. These agents are utilized for treating asthma but are associated with adverse outcomes. To ascertain the effects of persistent beta(2)AR activation on gene expression, cultured airway smooth muscle cells derived from wild-type (WT) and transgenic mice overexpressing beta(2)AR were subjected to DNA microarray analysis; 319 genes were increased and 164 were decreased. Differential expression was observed in genes from 22 Gene Ontology Slim categories, including those associated with ion transport and calcium ion binding. A 60% decrease (P = 0.008) in phospholamban (PLN), an intracellular Ca2+ concentration ([Ca2+](i))-handling protein that is at a signaling nodal point in cardiomyocytes, was observed in beta(2)AR-overexpressing cells and confirmed at the protein level. To isolate the physiological effect of decreased PLN in airway smooth muscle, airway contraction and relaxation responses were studied in WT and PLN-/- mice. PLN-/- mice had a markedly reduced constrictive response to methacholine. In contrast, the bronchodilatory effect of beta-agonist was not different between WT and PLN-/- mice. These results revealed an unanticipated therapeutic effect of beta-agonists, PLN downregulation, which acts to decrease airway hyperreactivity. Thus agents that inhibit PLN may act synergistically with the bronchodilating action of beta-agonists. A number of other genes related to [Ca2+](i) are also differentially regulated by beta(2)AR activity, some of which may act to oppose, or augment, the efficacy of chronic beta-agonists. These genes or pathways may also represent additional targets in the treatment of asthma and related obstructive lung diseases.