Carbonic anhydrase and soluble adenylate cyclase regulation of cystic fibrosis cellular phenotypes.
Carbonic anhydrase and soluble adenylate cyclase regulation of cystic fibrosis cellular phenotypes.
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DOI：
10.1152/ajplung.00022.2021
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发表时间：
2022-03-01
期刊：
影响因子：
--
通讯作者：
Kelley TJ
中科院分区：
文献类型：
--
作者：
Boyne K;Corey DA;Zhao P;Lu B;Boron WF;Moss FJ;Kelley TJ
囊性纤维化（CF）上皮细胞的细胞生物学的几个方面发生改变，包括脂质调节受损、细胞内转运中断和微管调节受损。目前尚不清楚囊性纤维化跨膜传导调节因子（CFTR）功能的丧失如何导致这些差异。据推测，CFTR功能的丧失会导致碳酸酐酶（CA）活性调节的改变，从而导致细胞表型变化。在本研究中，证明了在CF模型细胞、原代小鼠鼻上皮（MNE）细胞、切除的MNE组织和原代人鼻上皮细胞中CA 2蛋白表达降低（P < 0.05）。这对应于通过qPCR测量的CA 2 RNA表达的降低以及原代CF MNE中CA活性的总体降低。向WT MNE细胞中添加CFTR抑制剂-172 ≥24 h模拟CF细胞中CA 2的蛋白表达显著降低。用CA活性激活剂l-苯丙氨酸（L-Phe）处理CF细胞，通过以依赖于可溶性腺苷酸环化酶（sAC）的方式影响微管调节来恢复内体转运。这种作用可以用CA 2选择性抑制剂多佐胺阻断。这些数据表明，CFTR功能的丧失导致CA 2表达的降低，从而导致在CF中观察到的下游细胞信号传导改变。
Several aspects of the cell biology of cystic fibrosis (CF) epithelial cells are altered including impaired lipid regulation, disrupted intracellular transport, and impaired microtubule regulation. It is unclear how the loss of cystic fibrosis transmembrane conductance regulator (CFTR) function leads to these differences. It is hypothesized that the loss of CFTR function leads to altered regulation of carbonic anhydrase (CA) activity resulting in cellular phenotypic changes. In this study, it is demonstrated that CA2 protein expression is reduced in CF model cells, primary mouse nasal epithelial (MNE) cells, excised MNE tissue, and primary human nasal epithelial cells (P < 0.05). This corresponds to a decrease in CA2 RNA expression measured by qPCR as well as an overall reduction in CA activity in primary CF MNEs. The addition of CFTR-inhibitor-172 to WT MNE cells for ≥24 h mimics the significantly lower protein expression of CA2 in CF cells. Treatment of CF cells with l-phenylalanine (L-Phe), an activator of CA activity, restores endosomal transport through an effect on microtubule regulation in a manner dependent on soluble adenylate cyclase (sAC). This effect can be blocked with the CA2-selective inhibitor dorzolamide. These data suggest that the loss of CFTR function leads to the decreased expression of CA2 resulting in the downstream cell signaling alterations observed in CF.
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影响因子：
4.6
作者：
Rosenjack, Julie;Hodges, Craig A.;Kelley, Thomas J.
通讯作者：
Kelley, Thomas J.
DOI：
10.1152/ajplung.00411.2012
发表时间：
2013-09-01
影响因子：
4.9
作者：
Rymut, Sharon M.;Harker, Alyssa;Kelley, Thomas J.
通讯作者：
Kelley, Thomas J.
影响因子：
4.6
作者：
Rymut, Sharon M.;Corey, Deborah A.;Hodges, Craig A.
通讯作者：
Hodges, Craig A.
DOI：
10.1007/978-1-61779-117-8_30
发表时间：
2011-01-01
期刊：
CYSTIC FIBROSIS: DIAGNOSIS AND PROTOCOLS, VOL I: APPROACHES TO STUDY AND CORRECT CFTR DEFECTS
影响因子：
--
作者：
Hug, Martin J.;Clarke, Lane L.;Gray, Michael A.
通讯作者：
Gray, Michael A.
DOI：
10.1152/ajplung.90402.2008
发表时间：
2008-11-01
影响因子：
4.9
作者：
Manson, Mary E.;Corey, Deborah A.;Kelley, Thomas J.
通讯作者：
Kelley, Thomas J.