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CFTR 和 TMEM16A(ANO1)通过 EPAC1 和 ADCY1 进行区室化串扰。

Compartmentalized crosstalk of CFTR and TMEM16A (ANO1) through EPAC1 and ADCY1.

机构信息

University of Lisboa, Faculty of Sciences, BioISI - Biosystems & Integrative Sciences Institute, Campo Grande, C8, 1749-016 Lisboa, Portugal.

Institut für Physiologie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.

出版信息

Cell Signal. 2018 Apr;44:10-19. doi: 10.1016/j.cellsig.2018.01.008. Epub 2018 Jan 10.

Abstract

Airway epithelial cells express both Ca activated TMEM16A/ANO1 and cAMP activated CFTR anion channels. Previous work suggested a significant crosstalk of intracellular Ca and cAMP signaling pathways, leading to activation of both chloride channels. We demonstrate that in airway epithelial cells, stimulation of purinergic or muscarinic G-protein coupled receptors (GPCRs) activates TMEM16A and CFTR. Additional expression of G and phospholipase C coupled GPCRs strongly enhanced the crosstalk between Ca- and cAMP-dependent signaling. Knockdown of endogenous GRCRs attenuated crosstalk and functional coupling between TMEM16A and CFTR. The number of receptors did not affect expression or membrane localization of TMEM16A or CFTR, but controlled assembly of the local signalosome. GPCRs translocate Ca-sensitive adenylate cyclase type 1 (ADCY1) and exchange protein directly activated by cAMP (EPAC1) to particular plasma membrane domains containing GPCRs, CFTR and TMEM16A, thereby producing compartmentalized Ca and cAMP signals and significant crosstalk. While biosynthesis and membrane trafficking of CFTR requires a functional Golgi apparatus, maturation and membrane trafficking of TMEM16A may occur independent of the Golgi. Because Ca activated TMEM16A currents are only transient, continuous Cl secretion by airway epithelial cells requires CFTR. The present data also explain why receptor-dependent activation of TMEM16A is more efficient than direct stimulation by Ca.

摘要

气道上皮细胞表达钙激活的 TMEM16A/ANO1 和 cAMP 激活的 CFTR 阴离子通道。先前的工作表明,细胞内 Ca 和 cAMP 信号通路之间存在显著的串扰,导致两种氯离子通道的激活。我们证明,在气道上皮细胞中,嘌呤能或毒蕈碱 G 蛋白偶联受体(GPCR)的刺激激活 TMEM16A 和 CFTR。额外表达 G 和磷酯酶 C 偶联的 GPCR 强烈增强了 Ca 和 cAMP 依赖性信号之间的串扰。内源性 GCRCR 的敲低减弱了 TMEM16A 和 CFTR 之间的串扰和功能偶联。受体的数量不影响 TMEM16A 或 CFTR 的表达或膜定位,但控制局部信号体的组装。GPCR 将 Ca 敏感的腺苷酸环化酶 1(ADCY1)和 cAMP 直接激活的交换蛋白(EPAC1)易位到含有 GPCR、CFTR 和 TMEM16A 的特定质膜域,从而产生局部化的 Ca 和 cAMP 信号和显著的串扰。虽然 CFTR 的生物合成和膜运输需要功能性高尔基体,但 TMEM16A 的成熟和膜运输可能独立于高尔基体。由于 Ca 激活的 TMEM16A 电流是瞬时的,气道上皮细胞的持续 Cl 分泌需要 CFTR。本数据还解释了为什么受体依赖性的 TMEM16A 激活比直接的 Ca 刺激更有效。

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