A2 adenosine receptors regulate CFTR through PKA and PLA2
A2 adenosine receptors regulate CFTR through PKA and PLA2
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DOI：
10.1152/ajplung.2002.282.1.l12
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发表时间：
2002-01-01
影响因子：
4.9
通讯作者：
Clancy, JP
中科院分区：
文献类型：
--
作者：
Cobb, BR;Ruiz, F;Clancy, JP
我们在体外和体内研究了腺苷（Ado）对囊性纤维化跨膜传导调节因子（CFTR）的激活作用。在Calu - 3、IB - 3 - 1、COS - 7和原代人气道细胞中鉴定出了A(2B)腺苷受体。腺苷提高了Calu - 3、IB - 3 - 1和COS - 7细胞中的环磷腺苷酸（cAMP）水平，并激活了Calu - 3细胞中依赖蛋白激酶A的卤化物外流。腺苷促进了Calu - 3细胞中花生四烯酸的释放，并且磷脂酶A(2)（PLA(2)）抑制剂阻断了在表达CFTR的Calu - 3和COS - 7细胞中腺苷激活的卤化物外流。毛喉素和β(2) - 肾上腺素能受体刺激的外流不受相同处理的影响。在Calu - 3、IB - 3 - 1和COS - 7细胞中鉴定出了胞质磷脂酶A(2)（cPLA(2)），但cPLA(2)抑制剂不影响腺苷刺激的cAMP浓度。在cftr(+)和cftr(-/-)小鼠中，腺苷刺激了鼻腔氯离子分泌，该分泌依赖于CFTR，并且对A(2)受体和PLA(2)阻断敏感。在瞬时表达ΔF508 CFTR的COS - 7细胞中，腺苷激活了卤化物外流。当与花生四烯酸和磷酸二酯酶抑制剂联合使用时，腺苷还激活了依赖G551D CFTR的卤化物外流。总之，PLA(2)和蛋白激酶A都有助于A(2)受体对CFTR的激活，并且该信号通路的组分可以增强野生型和突变型CFTR的活性。
We investigated adenosine (Ado) activation of the cystic fibrosis transmembrane conductance regulator (CFTR) in vitro and in vivo. A(2B) Ado receptors were identified in Calu-3, IB-3-1, COS-7, and primary human airway cells. Ado elevated cAMP in Calu-3, IB-3-1, and COS-7 cells and activated protein kinase A-dependent halide efflux in Calu-3 cells. Ado promoted arachidonic acid release from Calu-3 cells, and phospholipase A(2) (PLA(2)) inhibition blocked Ado-activated halide efflux in Calu-3 and COS-7 cells expressing CFTR. Forskolin- and beta (2)-adrenergic receptor-stimulated efflux were not affected by the same treatment. Cytoplasmic PLA(2) (cPLA(2)) was identified in Calu-3, IB-3-1, and COS-7 cells, but cPLA(2) inhibition did not affect Ado-stimulated cAMP concentrations. In cftr(+) and cftr(-/-) mice, Ado stimulated nasal Cl- secretion that was CFTR dependent and sensitive to A(2) receptor and PLA(2) blockade. In COS-7 cells transiently expressing Delta F508 CFTR, Ado activated halide efflux. Ado also activated G551D CFTR-dependent halide efflux when combined with arachidonic acid and phosphodiesterase inhibition. In conclusion, PLA(2) and protein kinase A both contribute to A(2) receptor activation of CFTR, and components of this signaling pathway can augment wild-type and mutant CFTR activity.