RRC ID 67707
Author Narita K, Sasamoto S, Koizumi S, Okazaki S, Nakamura H, Inoue T, Takeda S.
Title TRPV4 regulates the integrity of the blood-cerebrospinal fluid barrier and modulates transepithelial protein transport.
Journal FASEB J
Abstract 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 α-2-macroglobulin (A2M). Overall, this study demonstrated a novel physiologic function of TRPV4 in the regulation of BCSFB permeability.
Volume 29(6)
Pages 2247-59
Published 2015-6-1
DOI 10.1096/fj.14-261396
PII fj.14-261396
PMID 25681460
MeSH Animals Blood-Brain Barrier / metabolism* Blotting, Western Calcium / metabolism Cells, Cultured Cerebrospinal Fluid / metabolism* Choroid Plexus / cytology Epithelial Cells / metabolism* Humans Leucine / analogs & derivatives Leucine / pharmacology Mice Microscopy, Confocal Phosphorylation / drug effects Primary Cell Culture Protein Transport / drug effects Serine / metabolism Sulfonamides / pharmacology Swine TRPV Cation Channels / agonists TRPV Cation Channels / antagonists & inhibitors TRPV Cation Channels / metabolism* Threonine / metabolism alpha-Macroglobulins / metabolism
IF 4.966
Human and Animal Cells 293(RCB1637)