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T 型钙通道 CACNA1H 在气管小管发生过程中平滑肌细胞骨架组织所必需的。

The T-Type Calcium Channel CACNA1H is Required for Smooth Muscle Cytoskeletal Organization During Tracheal Tubulogenesis.

机构信息

State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, 510182, P. R. China.

Guangzhou National Laboratory, Guangzhou International Bio Island, No. 9 XingDaoHuanBei Road, Guangzhou, Guangdong Province, 510005, P. R. China.

出版信息

Adv Sci (Weinh). 2024 Nov;11(44):e2308622. doi: 10.1002/advs.202308622. Epub 2024 Oct 3.

DOI:10.1002/advs.202308622
PMID:39360593
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11600216/
Abstract

Abnormalities of tracheal smooth muscle (SM) formation are associated with several clinical disorders including tracheal stenosis and tracheomalacia. However, the cellular and molecular mechanisms underlying tracheal SM formation remain poorly understood. Here, it is shown that the T-type calcium channel CACNA1H is a novel regulator of tracheal SM formation and contraction. Cacna1h in an ethylnitrosourea forward genetic screen for regulators of respiratory disease using the mouse as a model is identified. Cacna1h mutants exhibit tracheal stenosis, disorganized SM and compromised tracheal contraction. CACNA1H is essential to maintain actin polymerization, which is required for tracheal SM organization and tube formation. This process appears to be partially mediated through activation of the actin regulator RhoA, as pharmacological increase of RhoA activity ameliorates the Cacna1h-mutant trachea phenotypes. Analysis of human tracheal tissues indicates that a decrease in CACNA1H protein levels is associated with congenital tracheostenosis. These results provide insight into the role for the T-type calcium channel in cytoskeletal organization and SM formation during tracheal tube formation and suggest novel targets for congenital tracheostenosis intervention.

摘要

气管平滑肌（SM）形成异常与几种临床疾病有关，包括气管狭窄和气管软化。然而，气管 SM 形成的细胞和分子机制仍知之甚少。本文显示 T 型钙通道 CACNA1H 是气管 SM 形成和收缩的新型调节剂。在使用小鼠作为模型的呼吸疾病的乙基亚硝脲正向遗传筛选中鉴定出 CACNA1H 是一种新型的气管 SM 形成和收缩的调节剂。Cacna1h 突变体表现出气管狭窄、SM 组织紊乱和气管收缩受损。CACNA1H 对于维持肌动蛋白聚合是必需的，这是气管 SM 组织和管形成所必需的。这一过程似乎部分通过激活肌动蛋白调节剂 RhoA 来介导，因为 RhoA 活性的药理学增加可以改善 Cacna1h 突变体的气管表型。对人气管组织的分析表明，CACNA1H 蛋白水平的降低与先天性气管狭窄有关。这些结果为 T 型钙通道在气管管形成过程中细胞骨架组织和 SM 形成中的作用提供了深入了解，并为先天性气管狭窄的干预提供了新的靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/03e16509ff7f/ADVS-11-2308622-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/8181374974f3/ADVS-11-2308622-g005.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/117d459be1c1/ADVS-11-2308622-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/8d0be9075541/ADVS-11-2308622-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/4b196f80d1e8/ADVS-11-2308622-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/d683fe3beb10/ADVS-11-2308622-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/d826b22ffc82/ADVS-11-2308622-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/03e16509ff7f/ADVS-11-2308622-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/8181374974f3/ADVS-11-2308622-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/03bef8a0e296/ADVS-11-2308622-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/117d459be1c1/ADVS-11-2308622-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/8d0be9075541/ADVS-11-2308622-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/4b196f80d1e8/ADVS-11-2308622-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/d683fe3beb10/ADVS-11-2308622-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/d826b22ffc82/ADVS-11-2308622-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b560/11600216/03e16509ff7f/ADVS-11-2308622-g006.jpg

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