TRPV4 regulates the integrity of the blood-cerebrospinal fluid barrier and modulates transepithelial protein transport
TRPV4 regulates the integrity of the blood-cerebrospinal fluid barrier and modulates transepithelial protein transport
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DOI：
10.1096/fj.14-261396
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发表时间：
2015-06-01
期刊：
影响因子：
4.8
通讯作者：
Takeda, Sen
中科院分区：
文献类型：
--
作者：
Narita, Keishi;Sasamoto, Shohei;Takeda, Sen
物质从体循环扩散到中枢神经系统（CNS）受到血脑屏障（BBB）和血脑脊髓液屏障（BCSFB）的限制。脑室的脉络丛上皮细胞（CPEC）构成BCSFB，并调节血浆蛋白以及免疫细胞向CNS结缔组织的浸润。屏障功能在病理条件下改变。然而，BCSFB的调节机制尚未完全了解。在这里，我们研究了瞬时受体电位香草酸4（TRPV 4），一个多模态门控二价阳离子通道，在CPECs中高度表达的功能。TRPV 4广泛定位于猪CPEC的顶膜上，与其他细胞类型上发现的强烈纤毛定位相反。用TRPV 4特异性激动剂GSK 1016790 A（GSK; EC 50 34 nM）处理诱导了强烈的钙内流和立即的丝氨酸/苏氨酸蛋白磷酸化。激动剂处理诱导丝状肌动蛋白的量显著减少，并在10-20分钟内分解细胞连接。相比之下，用TRPV 4特异性拮抗剂HC 067047（HC; IC 50 74 nM）抑制基础TRPV 4活性，可降低α-2-巨球蛋白（A2 M）的基底外侧至顶端转运。总的来说，这项研究证明了TRPV 4在调节BCSFB渗透性方面的新生理功能。
The diffusion of materials from systemic circulation to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). Choroid plexus epithelial cells (CPECs) of the brain ventricles constitute the BCSFB and regulate the infiltration of plasma proteins as well as immune cells into the interstitium of the CNS. The barrier function is altered in pathologic conditions. However, the regulatory mechanism of BCSFB is not fully understood. Here, we investigated the function of transient receptor potential vanilloid 4 (TRPV4), a polymodally gated divalent cation channel that is highly expressed in CPECs. TRPV4 was localized broadly on the apical membrane in swine CPECs, in contrast with an intense ciliary localization found on other cell types. Treatment with the TRPV4-specific agonist, GSK1016790A (GSK; EC50 34 nM), induced a robust calcium influx and an immediate serine/threonine protein phosphorylation. The agonist treatment induced a marked decrease in the amount of filamentous actin and disintegrated the cell junctions in 10-20 minutes. In contrast, inhibition of the basal TRPV4 activity with the TRPV4-specific antagonist, HC067047 (HC; IC50 74 nM), reduced the basolateral-to-apical transport of alpha-2-macroglobulin (A2M). Overall, this study demonstrated a novel physiologic function of TRPV4 in the regulation of BCSFB permeability.