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胆管细胞中肌醇 1,4,5-三磷酸受体 3 周边靶向的分子决定因素。

Molecular determinants of peri-apical targeting of inositol 1,4,5-trisphosphate receptor type 3 in cholangiocytes.

机构信息

Section of Digestive Diseases, Internal MedicineYale UniversityNew HavenConnecticutUSA.

Department of Biochemistry and ImmunologyFederal University of Minas Gerais (UFMG)Belo HorizonteMGBrazil.

出版信息

Hepatol Commun. 2022 Oct;6(10):2748-2764. doi: 10.1002/hep4.2042. Epub 2022 Jul 19.

DOI:10.1002/hep4.2042
PMID:35852334
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9512452/
Abstract

Fluid and bicarbonate secretion is a principal function of cholangiocytes, and impaired secretion results in cholestasis. Cholangiocyte secretion depends on peri-apical expression of the type 3 inositol trisphosphate receptor (ITPR3), and loss of this intracellular Ca release channel is a final common event in most cholangiopathies. Here we investigated the mechanism by which ITPR3 localizes to the apical region to regulate secretion. Isolated bile duct units, primary mouse cholangiocytes, and polarized Madin-Darby canine kidney (MDCK) cells were examined using a combination of biochemical and fluorescence microscopy techniques to investigate the mechanism of ITPR3 targeting to the apical region. Apical localization of ITPR3 depended on the presence of intact lipid rafts as well as interactions with both caveolin 1 (CAV1) and myosin heavy chain 9 (MYH9). Chemical disruption of lipid rafts or knockdown of CAV1 or MYH9 redistributed ITPR3 away from the apical region. MYH9 interacted with the five c-terminal amino acids of the ITPR3 peptide. Disruption of lipid rafts impaired Ca signaling, and absence of CAV1 impaired both Ca signaling and fluid secretion. Conclusion: A cooperative mechanism involving MYH9, CAV1, and apical lipid rafts localize ITPR3 to the apical region to regulate Ca signaling and secretion in cholangiocytes.

摘要

液体和碳酸氢盐的分泌是胆管细胞的主要功能，分泌功能受损会导致胆汁淤积。胆管细胞的分泌依赖于顶端周缘表达的三磷酸肌醇受体 3（ITPR3），而这种细胞内钙释放通道的丧失是大多数胆管疾病的共同最终事件。在这里，我们研究了 ITPR3 定位到顶端区域以调节分泌的机制。使用生化和荧光显微镜技术的组合，研究了分离的胆管单位、原代小鼠胆管细胞和极化的 Madin-Darby 犬肾 (MDCK) 细胞，以研究 ITPR3 靶向顶端区域的机制。ITPR3 的顶端定位取决于完整的脂筏的存在以及与 caveolin 1 (CAV1) 和肌球蛋白重链 9 (MYH9) 的相互作用。脂筏的化学破坏或 CAV1 或 MYH9 的敲低会将 ITPR3 重新分布到顶端区域之外。MYH9 与 ITPR3 肽的五个 C 末端氨基酸相互作用。脂筏的破坏会损害钙信号转导，而 CAV1 的缺失会损害钙信号转导和液体分泌。结论：一种涉及 MYH9、CAV1 和顶端脂筏的协作机制将 ITPR3 定位到顶端区域，以调节胆管细胞中的钙信号转导和分泌。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/197ae8987f7c/HEP4-6-2748-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/02e126a7714e/HEP4-6-2748-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/95bee41034bb/HEP4-6-2748-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/0f9508f49ea1/HEP4-6-2748-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/00d261388fd5/HEP4-6-2748-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/6e56bb90ec5f/HEP4-6-2748-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/d50a80ab5853/HEP4-6-2748-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/99ce83c2206d/HEP4-6-2748-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/197ae8987f7c/HEP4-6-2748-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/02e126a7714e/HEP4-6-2748-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/95bee41034bb/HEP4-6-2748-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/0f9508f49ea1/HEP4-6-2748-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/00d261388fd5/HEP4-6-2748-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/6e56bb90ec5f/HEP4-6-2748-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/d50a80ab5853/HEP4-6-2748-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/99ce83c2206d/HEP4-6-2748-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/845e/9512452/197ae8987f7c/HEP4-6-2748-g002.jpg

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