Functional Characterization of Rat Brain-specific Organic Anion Transporter (Oatp14) at the Blood-Brain Barrier

Sugiyama, Daisuke; Kusuhara, Hiroyuki; Taniguchi, Hirokazu; Ishikawa, Shumpei; Nozaki, Yoshitane; Aburatani, Hiroyuki; Sugiyama, Yuichi

doi:10.1074/jbc.m306933200

Cited by 257 publications

(189 citation statements)

References 32 publications

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“…Oatp2 and oatp14 have been reported to be expressed in brain capillary endothelial cells (Gao et al 1999;Sugiyama et al 2003). Oatp3 and these transporters have similar substrate specificity, so that oatp2, 3 and 14 are likely to cooperate in BBB transport.…”

Section: Discussionmentioning

confidence: 99%

“…Oatp2 and oatp14 are expressed at brain capillaries and choroid plexus, which form the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB), respectively (Gao et al 1999;Sugiyama et al 2003). We have reported that oatp3 is localized at the rat choroid plexus (Ohtsuki et al 2003) and this finding raises the issue of whether oatp3 is expressed at the brain capillaries.…”

mentioning

confidence: 99%

“…We have reported that oatp3 is localized at the rat choroid plexus (Ohtsuki et al 2003) and this finding raises the issue of whether oatp3 is expressed at the brain capillaries. Oatp3 accepts prostaglandin E 2 (PGE 2 ) as a substrate, whereas oatp2 and oatp14 do not (Cattori et al 2001;Sugiyama et al 2003). PGE 2 functions as a mediator of peripheral inflammation to the brain across the BBB (Engblom et al 2002).…”

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confidence: 99%

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Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells

Ohtsuki

Takizawa

Takanaga

et al. 2004

Journal of Neurochemistry

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Organic anion transporting polypeptide 3 (oatp3) transports various CNS-acting endogenous compounds, including thyroid hormones and prostaglandin E 2 , between extra-and intracellular spaces, suggesting a possible role in CNS function. The purpose of this study was to clarify the expression and localization of oatp3 in the mouse brain. RT-PCR analysis revealed that oatp3 mRNA is expressed in brain capillary-rich fraction, conditionally immortalized brain capillary endothelial cells, choroid plexus, brain and lung, but not in liver or kidney, where oatp1, 2 and 5 mRNAs were detected. Immunohistochemical analysis with anti-oatp3 antibody suggests that oatp3 protein is localized at the brush-border membrane of mouse choroid plexus epithelial cells. Furthermore, intense immunoreactivity was detected in neural cells in the border region between hypothalamus and thalamus, and in the olfactory bulb. Immunoreactivity was also detected in brain capillary endothelial cells in the cerebral cortex. These localizations in the mouse brain suggest that oatp3 plays roles in blood-brain and -cerebrospinal fluid barrier transport of organic anions and signal mediators, and in hormone uptake by neural cells. Keywords: blood-brain barrier, choroid plexus, hypothalamus, olfactory bulb, organic anion transporting polypeptide 3. Organic anion transporting polypeptide 3 (oatp3; Slc21a7) mediates sodium-independent transport of a wide variety of amphipathic organic compounds, including opioid peptides, neurosteroid conjugates, thyroid hormones (THs), bile acids and drugs, such as fexofenadine (Abe et al. 1998;Dresser et al. 2002;Hagenbuch and Meier 2003). Since many of these substrates are active in the CNS, oatp3 may play a role in the control of CNS functions.THs play an important role in normal CNS development and maturation. The expression of TH receptors was detected in adult brain (Puymirat et al. 1991), and hypothyroidism induces changes in the neuronal morphology of adult rat brain (Ruiz-Marcos et al. 1980) and affects memory in human patients (Burmeister et al. 2001). THs interact with nuclear TH receptors to express their effects. Although it was believed that THs enter target cells by passive diffusion, the recent reports have demonstrated that their cellular uptake by cells, including neurons and astrocytes, is carrier-mediated (Francon et al. 1989;Chantoux et al. 1995;Hennemann et al. 2001). Although roles of oatp family members in neural cells have not been considered yet, it is conceivable that oatps mediate TH uptake of the target cells in the brain.Expression of oatp3 mRNA in rat brain has been detected by means of RNase protection assay and RT-PCR analysis (Walters et al. 2000;Ohtsuki et al. 2003). Since oatp3 mediates transport of THs, such as triiodothyronine (T 3 ) and thyroxine (T 4 ) (Abe et al. 1998), we hypothesize that oatp3 is expressed at the neural cells and mediates their TH uptake. Received January 13, 2004; revised manuscript received March 19, 2004; accepted April 8, 2004.Address correspondence ...

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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confidence: 99%

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Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells

Ohtsuki

Takizawa

Takanaga

et al. 2004

Journal of Neurochemistry

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“…However, T4 can still enter the brain even in the absence of MCT8 suggesting that at least in mice another transporter must exist for mediating the uptake of T4 at the blood-brain barrier. A good candidate for this transit is Oatp1c1, a member of the organic anion transporting polypeptide family which not only exhibits a high degree of substrate specificity towards T4 (and the inactive metabolite rT3) but is also strongly expressed in capillary endothelial cells in the CNS (Sugiyama et al, 2003;Tohyama et al, 2004). Whether Oatpc1c1 is indeed the predominant T4 transporter at the blood-brain barrier can only by proven after the successful generation and characterization of a respective knockout mouse.…”

Section: Role Of Thyroid Hormone Transportersmentioning

confidence: 99%

Thyroid hormone action during brain development: More questions than answers

Horn

Heuer

2010

Molecular and Cellular Endocrinology

173

109

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“…Initial applications of the SSH methodology to the rat BBB led to the identification of a transcript, which encoded a protein with distant amino-acid homology to the organic anion transporting polypeptide type 2 (oatp2) (Li et al, 2001a(Li et al, , 2002. This orphan transporter was originally designated BBB-specific anion transporter type 1 (BSAT1) (Li et al, 2001a(Li et al, , 2002, and was subsequently shown to transport organic anions (Sugiyama et al, 2003), and was named oatp14, and finally designated Slco1c1 (Hagenbuch and Meier, 2003). Blood-brain barrier genomics investigations are viewed as a two-part process.…”

Section: Introductionmentioning

confidence: 99%

Blood—Brain Barrier Genomics and Cloning of a Novel Organic Anion Transporter

Cai¹,

Li²,

Boado³

et al. 2007

J Cereb Blood Flow Metab

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A novel organic anion transporter selectively expressed at the blood-brain barrier (BBB), originally designated BBB-specific anion transporter type 1 (BSAT1), and now classified as Slco1c1, has been cloned from a BBB genomics program as a partial cDNA; this study describes the cloning and expression of the full-length cDNA from a rat brain capillary cDNA library. Northern analysis revealed the selective expression of the transporter at the BBB, and the transporter was expressed after permanent transfection of human 293 cells with cDNA encoding either the full length or open reading frame mRNA. The full-length transporter cDNA was 2.6 kb, and the mRNA was highly expressed at the rat brain microvasculature, but not in kidney, liver, heart, or lung, or in glial cells or brain glial tumors. Blood-brain barrier-specific anion transporter type 1 expression in 293 cells was poor after the transfection of the full-length cDNA, whereas transporter expression in 293 cells was high after transfection of the open reading frame. The transporter showed asymmetric kinetic properties in comparison of the influx and efflux of model substrates, thyroxine (T4), triiodothyronine (T3), and estradiol-glucuronide (E2G). Thyroxine and T3 inhibited the influx of E2G, but E2G did not inhibit thyroxine influx, and T3 only weakly inhibited the influx of T4. Extracellular E2G stimulated the transefflux of intracellular T4. Blood-brain barrier-specific anion transporter type 1 is a novel organic anion transporter that is a sodium-independent exchanger that may participate in the active efflux of iodothyronines and steroid conjugates at the BBB.

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Functional Characterization of Rat Brain-specific Organic Anion Transporter (Oatp14) at the Blood-Brain Barrier

Cited by 257 publications

References 32 publications

Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells

Localization of organic anion transporting polypeptide 3 (oatp3) in mouse brain parenchymal and capillary endothelial cells

Thyroid hormone action during brain development: More questions than answers

Blood—Brain Barrier Genomics and Cloning of a Novel Organic Anion Transporter

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