A macromolecular complex of β2 adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA
A macromolecular complex of β2 adrenergic receptor, CFTR, and ezrin/radixin/moesin-binding phosphoprotein 50 is regulated by PKA
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DOI：
10.1073/pnas.0135434100
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发表时间：
2003-01-07
影响因子：
11.1
通讯作者：
Clancy, JP
中科院分区：
文献类型：
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作者：
Naren, AP;Cobb, B;Clancy, JP
已有研究表明，囊性纤维化跨膜传导调节因子(CFTR)和β(2)肾上腺素能受体(β(2)AR)均可通过其PDZ基序与Ezrin/Radioxin/Moesin结合的磷酸蛋白50(EBP50，也称为NHERF)结合。在这里，我们证明了β(2)是在呼吸道上皮细胞中表达的主要肾上腺素能受体亚型，它与CFTR共存于顶膜。β(2)AR刺激增加了呼吸道上皮细胞的CFTR活性，即对格列本脲敏感。从cftr中删除PDZ基序使通道在物理上和功能上与受体解偶联。这种解偶联是针对β(2)AR受体的，并不影响CFTR与其他受体的偶联(例如，腺苷受体途径)。生化研究表明，通过基于PDZ的相互作用，存在涉及CFTR-EBP50-β(2)AR的大分子复合体。该复合体的组装受PKA依赖的磷酸化调节。删除Cur的调控结构域取消了对复杂组装的PKA调控。这份报告总结了一个涉及CFTR的大分子信号复合体，其含义可能与CFTR功能障碍疾病有关。
It has been demonstrated previously that both the cystic fibrosis transmembrane conductance regulator (CFTR) and beta(2) adrenergic receptor (beta(2)AR) can bind ezrin/radixin/moesin-binding phosphoprotein 50 (EBP50, also referred to as NHERF) through their PDZ motifs. Here, we show that beta(2) is the major adrenergic receptor isoform expressed in airway epithelia and that it colocalizes with CFTR at the apical membrane. beta(2)AR stimulation increases CFTR activity, in airway epithelial cells, that is glybenclamide sensitive. Deletion of the PDZ motif from CFTR uncouples the channel from the receptor both physically and functionally. This uncoupling is specific to the beta(2)AR receptor and does not affect CFTR coupling to other receptors (e.g., adenosine receptor pathway). Biochemical studies demonstrate the existence of a macromolecular complex involving CFTR-EBP50-beta(2)AR through PDZ-based interactions. Assembly of the complex is regulated by PKA-dependent phosphorylation. Deleting the regulatory domain of CUR abolishes PKA regulation of complex assembly. This report summarizes a macromolecular signaling complex involving CFTR, the implications of which may be relevant to CFTR-dysfunction diseases.