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TRPV4 regulates the integrity of the blood‐cerebrospinal fluid barrier and modulates transepithelial protein transport
Author(s) -
Narita Keishi,
Sasamoto Shohei,
Koizumi Schuichi,
Okazaki Shizuka,
Nakamura Hideki,
Inoue Takafumi,
Takeda Sen
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.14-261396
Subject(s) - blood–brain barrier , choroid plexus , microbiology and biotechnology , tight junction , chemistry , trpv4 , barrier function , transient receptor potential channel , apical membrane , central nervous system , biology , endocrinology , receptor , biochemistry , membrane
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.—Narita, K., Sasamoto, S., Koizumi, S., Okazaki, S., Nakamura, H., Inoue, T., Takeda, S. TRPV4 regulates the integrity of the blood‐cerebrospinal fluid barrier and modulates transepithelial protein transport FASEB J. 29, 2247‐2259 (2015). www.fasebj.org