TY - JOUR
T1 - TRPV4 regulates the integrity of the blood-cerebrospinal fluid barrier and modulates transepithelial protein transport
AU - Narita, Keishi
AU - Sasamoto, Shohei
AU - Koizumi, Schuichi
AU - Okazaki, Shizuka
AU - Nakamura, Hideki
AU - Inoue, Takafumi
AU - Takeda, Sen
N1 - Publisher Copyright:
© FASEB.
PY - 2015/6/1
Y1 - 2015/6/1
N2 - The diffusion of materials from systemic circulation to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB) and the bloodcerebrospinal 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.Incontrast, inhibitionof 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.
AB - The diffusion of materials from systemic circulation to the central nervous system (CNS) is restricted by the blood-brain barrier (BBB) and the bloodcerebrospinal 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.Incontrast, inhibitionof 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.
KW - Actin
KW - Calcium imaging
KW - Subcellular localization
UR - http://www.scopus.com/inward/record.url?scp=84933564234&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84933564234&partnerID=8YFLogxK
U2 - 10.1096/fj.14-261396
DO - 10.1096/fj.14-261396
M3 - Article
C2 - 25681460
AN - SCOPUS:84933564234
SN - 0892-6638
VL - 29
SP - 2247
EP - 2259
JO - FASEB Journal
JF - FASEB Journal
IS - 6
M1 - 261396
ER -