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血管活性肠肽和囊性纤维化跨膜电导调节因子促进肠上皮样 Caco-2 单层细胞的跨上皮钙转运。

Vasoactive intestinal peptide and cystic fibrosis transmembrane conductance regulator contribute to the transepithelial calcium transport across intestinal epithelium-like Caco-2 monolayer.

机构信息

Faculty of Science, Center of Calcium and Bone Research (COCAB), Mahidol University, Bangkok, Thailand.

Faculty of Science, Department of Physiology, Mahidol University, Bangkok, Thailand.

出版信息

PLoS One. 2022 Nov 18;17(11):e0277096. doi: 10.1371/journal.pone.0277096. eCollection 2022.

DOI:10.1371/journal.pone.0277096
PMID:36399482
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9674163/
Abstract

Vasoactive intestinal peptide (VIP) as a neurocrine factor released by enteric neurons has been postulated to participate in the regulation of transcellular active calcium transport across intestinal epithelium, but the preceding evidence is scant and inconclusive. Herein, transepithelial calcium flux and epithelial electrical parameters were determined by Ussing chamber technique with radioactive tracer in the intestinal epithelium-like Caco-2 monolayer grown on Snapwell. After 3-day culture, Caco-2 cells expressed mRNA of calcium transporters, i.e., TRPV6, calbindin-D9k, PMCA1b and NCX1, and exhibited transepithelial resistance of ~200 Ω cm2, a characteristic of leaky epithelium similar to the small intestine. VIP receptor agonist was able to enhance transcellular calcium flux, whereas VIP receptor antagonist totally abolished calcium fluxes induced by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Since the intestinal cystic fibrosis transmembrane conductance regulator (CFTR) could be activated by VIP and calciotropic hormones, particularly parathyroid hormone, we sought to determine whether CFTR also contributed to the 1,25(OH)2D3-induced calcium transport. A selective CFTR inhibitor (20-200 μM CFTRinh-172) appeared to diminish calcium fluxes as well as transepithelial potential difference and short-circuit current, both of which indicated a decrease in electrogenic ion transport. On the other hand, 50 μM genistein-a molecule that could rapidly activate CFTR-was found to increase calcium transport. Our in silico molecular docking analysis confirmed direct binding of CFTRinh-172 and genistein to CFTR channels. In conclusion, VIP and CFTR apparently contributed to the intestinal calcium transport, especially in the presence of 1,25(OH)2D3, thereby supporting the existence of the neurocrine control of intestinal calcium absorption.

摘要

血管活性肠肽（VIP）作为一种肠神经元释放的神经内分泌因子，被推测参与调节肠道上皮细胞的跨细胞主动钙转运，但先前的证据很少且不确定。在此，通过放射性示踪剂在 Snapwell 上生长的类似肠上皮的 Caco-2 单层细胞的 Ussing 室技术，确定了跨上皮钙通量和上皮电参数。在 3 天的培养后，Caco-2 细胞表达了钙转运体的 mRNA，即 TRPV6、钙结合蛋白-D9k、PMCA1b 和 NCX1，并表现出约 200 Ω cm2 的跨上皮电阻，这是类似于小肠的渗漏上皮的特征。VIP 受体激动剂能够增强跨细胞钙通量，而 VIP 受体拮抗剂完全消除了 1,25-二羟维生素 D3 [1,25(OH)2D3] 诱导的钙通量。由于肠道囊性纤维化跨膜电导调节因子（CFTR）可以被 VIP 和钙调节激素激活，特别是甲状旁腺激素，我们试图确定 CFTR 是否也有助于 1,25(OH)2D3 诱导的钙转运。一种选择性的 CFTR 抑制剂（20-200 μM CFTRinh-172）似乎减少了钙通量以及跨上皮电位差和短路电流，这表明电致离子转运减少。另一方面，发现 50 μM 染料木黄酮——一种可以快速激活 CFTR 的分子——增加了钙转运。我们的计算机分子对接分析证实了 CFTRinh-172 和染料木黄酮与 CFTR 通道的直接结合。总之，VIP 和 CFTR 显然有助于肠道钙转运，特别是在存在 1,25(OH)2D3 的情况下，从而支持肠道钙吸收的神经内分泌控制的存在。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/5b412ff8dbb0/pone.0277096.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/5fa3be6807f0/pone.0277096.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/36caf4dbd664/pone.0277096.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/e27b3cb9f20c/pone.0277096.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/cc7f6f14ece9/pone.0277096.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/5b412ff8dbb0/pone.0277096.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/5fa3be6807f0/pone.0277096.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/36caf4dbd664/pone.0277096.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/e27b3cb9f20c/pone.0277096.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/cc7f6f14ece9/pone.0277096.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/7494/9674163/5b412ff8dbb0/pone.0277096.g005.jpg

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