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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Targeted transgenesis reveals discrete attenuator functions of GRK and PKA in airway β_2-adrenergic receptor physiologic signaling
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Targeted transgenesis reveals discrete attenuator functions of GRK and PKA in airway β_2-adrenergic receptor physiologic signaling

机译：靶向转基因揭示气道β_2-肾上腺素受体生理信号中GRK和PKA的离散衰减功能

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摘要

Phosphorylation by protein kinase A (PKA) and G protein-coupled receptor kinases (GRKs) desensitize β2-adrenergic receptor (β_2AR) signaling, and these are thought to be mechanisms involved with cell and organ homeostasis and tolerance to agonists. However, there is little direct evidence that these events are relevant to β_2AR physiological function, such as airway smooth muscle (ASM) relaxation leading to bronchodilation. To maintain cell- and receptor-specificity without altering the natural complement of kinases/ arrestins, transgenic mice were generated expressing the human WT and mutated β_2ARs lacking PKA and/or GRK phosphorylation sites on ASM at≈ 4-fold over background. Functional gains in response to β-agonist from the selective loss of these mechanisms were determined in mouse airways. Relaxation kinetics were altered in all mutant airways compared with β_2WT. At low receptor occupancy, β_2PKA(-) had enhanced agonist-promoted relaxation, while β_2GRK(-) airways were unaffected. In contrast, at saturating agonist concentrations, the greatest relaxation enhancement was with β_2GRK(-), with no evidence for additivity when PKA sites were also removed. For the full range of responses, the β_2PKA(-)/GRK(-) airways had the greatest relaxation efficiency, indicating a graded effect of GRKs as agonist concentration increased. ASM cAMP levels paralleled relaxation phenotypes. No interaction between PKA phosphorylation of β_2AR and GRK-promoted events was identified by β-arrestin-2 recruitment. Thus, these two mechanisms indeed impact a relevant β_2AR physiologic function, acting as attenuators of the acute response, and represent specific interfaces where adjunct therapy or biased ligands may improve β-agonist treatment of obstructive lung disease.
机译：蛋白激酶A（PKA）和G蛋白偶联受体激酶（GRKs）进行的磷酸化作用使β2-肾上腺素能受体（β_2AR）信号减弱，这被认为与细胞和器官体内稳态以及对激动剂的耐受性有关。但是，几乎没有直接证据表明这些事件与β_2AR生理功能有关，例如导致支气管扩张的气道平滑肌（ASM）松弛。为了维持细胞和受体的特异性而不改变激酶/抑制蛋白的天然补体，产生了转基因小鼠，其表达人WT和突变的β_2AR，其在ASM上缺乏PKA和/或GRK磷酸化位点，其背景约为背景的4倍。在小鼠呼吸道中确定了由于这些机制的选择性丧失而对β-激动剂起反应的功能增强。与β_2WT相比，所有突变气道的松弛动力学都发生了变化。在低受体占有率时，β_2PKA（-）增强了激动剂促进的舒张，而β_2GRK（-）气道未受影响。相反，在饱和激动剂浓度下，最大的弛豫增强是β_2GRK（-），而当PKA位点也被去除时，没有可加性的证据。对于整个反应范围，β_2PKA（-）/ GRK（-）气道具有最大的舒张效率，表明随着激动剂浓度的增加，GRK的分级效应。 ASM cAMP水平平行于松弛表型。通过β-arrestin-2募集，未鉴定出β_2AR的PKA磷酸化与GRK促进的事件之间存在相互作用。因此，这两种机制确实影响了相关的β_2AR生理功能，充当急性反应的衰减剂，并代表了辅助治疗或配体偏向可能改善阻塞性肺疾病的β激动剂治疗的特定界面。

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  • 作者

    Wayne C. H. Wang; Kathryn A. Mihlbachler; Alicyn C. Brunnett; Stephen B. Liggett;

  • 作者单位

    Cardiopulmonary Genomics Program, Department of Medicine, University of Maryland School of Medicine, 20 Penn Street, HSF-II, Baltimore, MD 21201;

    Cardiopulmonary Genomics Program, Department of Medicine, University of Maryland School of Medicine, 20 Penn Street, HSF-II, Baltimore, MD 21201;

    Cardiopulmonary Genomics Program, Department of Medicine, University of Maryland School of Medicine, 20 Penn Street, HSF-II, Baltimore, MD 21201;

    Cardiopulmonary Genomics Program, Department of Medicine, University of Maryland School of Medicine, 20 Penn Street, HSF-II, Baltimore, MD 21201;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    desensitization; adenylyl cyclase; smooth muscle; asthma;

    机译：脱敏;腺苷酸环化酶;平滑肌;哮喘;

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