Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells

Iwao, Beniko; Yara, Miki; Hara, Naomi; Kawai, Yuiko; Yamanaka, T.; Nishihara, Hiroshi; Inoue, Takeshi; Inazu, Masato

doi:10.1016/j.neuint.2015.12.011

Cited by 43 publications

(38 citation statements)

References 41 publications

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“…It should also be noted that, even though choline showed a mild inhibitory effect on the carnitine uptake in the present study, the Cl − -independent uptake profile and sensitivity profile to extracellular pH were not consistent with the properties of choline transporters 26) and choline transporter-like proteins, 27) respectively. Given that the known transporters cannot explain its uptake by 661W cells, it is reasonable to assume that at least one previously unidentified carnitine transporter is expressed in 661W cells, which raises the question as to what type of transporter it could be.…”

Section: Discussioncontrasting

confidence: 90%

Characterization of an L-Carnitine Transport System in Murine Photoreceptor Cell Line

Ohno

Otsuka

Nohara

et al. 2017

Biological & Pharmaceutical Bulletin

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While it is well known that L-carnitine [3-hydroxy-4-(trimethylazaniumyl)-butanoate] is an essential molecule for β-oxidation, it provides anti-oxidative effects as well. Since these effects have been observed in photoreceptor cells, the carnitine's intracellular concentration is considered to play a protective role against oxidative damage to those cells. However, even though its high hydrophilicity makes it likely that carnitine import is accomplished via a dedicated host transport system, the specific uptake process into those cells is currently unknown. Therefore, in this study, we sought to identify and characterize photoreceptor cell carnitine uptake transporter(s) utilizing 661W cells as a photoreceptor cell model. The results of our uptake assays showed that carnitine was transported into 661W cells in a saturable manner (K m 5.5 mM), and that the activity was susceptible to extracellular pH and Na . While these data suggest the involvement of a transporter in 661W cell carnitine uptake, the observed transport profile did not correspond to any of the currently known carnitine transporters such as organic cation/carnitine transporter 1 (Octn1), Octn2, Octn3, B 0, and Ct2. In fact, in our experiments, the mRNA expressions for such carnitine transporters in 661W cells were consistently very low and the carnitine transporter substrates did not inhibit the uptake activities. Taken as a whole, our results indicate that carnitine is transported into 661W cells in a carrier-mediated manner. However, since its transport modes cannot be fully explained by known carnitine transporters, it is highly likely that photoreceptor cells utilize a unique molecularly-based carnitine uptake system.

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Section: Discussioncontrasting

confidence: 90%

Characterization of an L-Carnitine Transport System in Murine Photoreceptor Cell Line

Ohno

Otsuka

Nohara

et al. 2017

Biological & Pharmaceutical Bulletin

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“…Recently, it was reported that choline transporterlike protein 1 (CTL1/SLC44A1) is highly expressed in plasma membrane of human brain microvascular endothelial cells, and is responsible for the uptake of extracellular choline. 32 However, as shown in Figure 6a, replacement of extracellular Na þ by choline þ had little effect on varenicline uptake, suggesting that CTL1 is unlikely to be involved. On the other hand, varenicline uptake was strongly inhibited by substrates and inhibitors of H þ /OC antiporter reported in previous studies (Table 1).…”

Section: Discussionmentioning

confidence: 89%

Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells

Kurosawa

Higuchi

Okura

et al. 2017

Journal of Pharmaceutical Sciences

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Varenicline is a selective partial αβ nicotinic acetylcholine receptor agonist, which is used to help achieve smoking cessation. Here, we investigated varenicline transport at the blood-brain barrier by means of in vivo microdialysis, in situ brain perfusion, and brain efflux index measurements in rats, and in vitro uptake studies in human brain capillary endothelial cells. Microdialysis demonstrated that varenicline is actively transported from blood to brain in rats. Blood-to-brain uptake transport of varenicline, as measured by the in situ brain perfusion technique, was strongly inhibited by diphenhydramine, a potent inhibitor of proton-coupled organic cation (H/OC) antiporter. However, brain efflux index study showed that brain-to-blood efflux transport of varenicline was not inhibited by diphenhydramine. In human brain capillary endothelial cells, varenicline was taken up time- and concentration-dependently. The uptake was dependent on an oppositely directed proton gradient, but was independent of extracellular sodium and membrane potential. The uptake was inhibited by a metabolic inhibitor, and by substrates of H/OC antiporter, but not by substrates or inhibitors of OCTs, OCTNs, PMAT, and MATE1, which are known organic cation transporters. The present results suggest that the H/OC antiporter contributes predominantly to varenicline uptake at the blood-brain barrier.

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“…Slc44a1 (also known as CLT1) is a member of the low-affinity Na + -independent choline transporter-like protein family (Traiffort et al, 2013). Because this protein is known to be expressed in human brain microvasculature (Iwao et al, 2016), we explored the vascular changes in Slc44a1- /- mutants in more detail. Quantification of vascular density showed that the intermediate and deep vascular layers both had markedly more branch points relative to wild-type mice.…”

Section: Resultsmentioning

confidence: 99%

Rapid and Integrative Discovery of Retina Regulatory Molecules

et al. 2018

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SUMMARY Retinal function relies on precisely organized neurons and synapses and a properly patterned vasculature to support them. Alterations in these features can result in vision loss. However, our understanding of retinal organization pathways remains incomplete because of a lack of methods to rapidly identify neuron and vasculature regulators in mammals. Here we developed a pipeline for the identification of neural and synaptic integrity genes by high-throughput retinal screening (INSiGHT) that analyzes candidate expression, vascular patterning, cellular organization, and synaptic arrangement. Using this system, we examined 102 mutant mouse lines and identified 16 unique retinal regulatory genes. Fifteen of these candidates are identified as novel retina regulators, and many (9 of 16) are associated with human neural diseases. These results expand the genetic landscape involved in retinal circuit organization and provide a road map for continued discovery of mammalian retinal regulators and disease-causing alleles.

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Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells

Cited by 43 publications

References 41 publications

Characterization of an L-Carnitine Transport System in Murine Photoreceptor Cell Line

Characterization of an L-Carnitine Transport System in Murine Photoreceptor Cell Line

Involvement of Proton-Coupled Organic Cation Antiporter in Varenicline Transport at Blood-Brain Barrier of Rats and in Human Brain Capillary Endothelial Cells

Rapid and Integrative Discovery of Retina Regulatory Molecules

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