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The regulation of transport mechanisms at brain barriers must be thoroughly understood, so that novel strategies for improving drug delivery to the brain can be designed. The blood-cerebrospinal fluid barrier (BCSFB) established by the choroid plexus (CP) epithelial cells has been poorly studied in this regard despite its relevance for the protection of the central nervous system (CNS). This study assessed the role of bitter taste receptors (TAS2Rs), TAS2R14 and TAS2R39, in the transport of resveratrol across CP epithelial cells using an in vitro model of the human BCSFB. Both receptors are expressed in human CP cells and known to bind resveratrol. First, Ca2+ imaging assays demonstrated that resveratrol specifically activates the TAS2R14 receptor, but not TAS2R39, in these human CP epithelial cells. Then, we proceeded with permeation studies that showed resveratrol can cross the human BCSFB, from the blood to the CSF side and that TAS2R14 knockdown decreased the transport of resveratrol across these cells. Conversely, inhibition of efflux transporters ABCC1, ABCC4 or ABCG2 also restrained the transport of resveratrol across these cells. Interestingly, resveratrol upregulated the expression of ABCG2 located at the apical membrane of the cells via TAS2R14, whereas ABCC1 and ABCC4 at the basolateral membrane of the cells were not affected. Altogether, our study demonstrates that the BCSFB is a gateway for resveratrol entrance into the CNS and that the receptor TAS2R14 regulates its transport by regulating the action of efflux transporters at CP epithelial cells. Copyright © 2020 Elsevier Inc. All rights reserved.


Ana C Duarte, Tiago Rosado, Ana R Costa, José Santos, Eugénia Gallardo, Telma Quintela, Hiroshi Ishikawa, Christian Schwerk, Horst Schroten, Isabel Gonçalves, Cecília R A Santos. The bitter taste receptor TAS2R14 regulates resveratrol transport across the human blood-cerebrospinal fluid barrier. Biochemical pharmacology. 2020 Jul;177:113953

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PMID: 32272108

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