Brain interstitial fluid glutamine homeostasis is controlled by blood–brain barrier SLC7A5/LAT1 amino acid transporter

Dolgodilina, Elena; Imobersteg, Stefan; Laczkó, Endre; Welt, Tobias; Verrey, François; Makrides, Victoria

doi:10.1177/0271678x15609331

Cited by 70 publications

(70 citation statements)

References 40 publications

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“…Furthermore, physiological parameters such as blood AA levels support the idea that Xenopus transporters likely evolved in similar environments as mammalian AATs. For example, Leu concentration in Xenopus plasma was reported as 150 μM39 which is consistent with values reported for humans2 and mice40. Additionally, in vitro studies using Xenopus intestines demonstrate similar drug permeabilities as human intestines indicating frog transporter kinetic and substrate specificities mimic human transporter activity41.Salmon SLC6A19/B 0 AT1 expressed in Xenopus oocytes was found to have similar kinetics as mouse B 0 AT142.…”

Section: Discussionsupporting

confidence: 80%

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

Taslimifar

Oparija

Verrey

et al. 2017

Sci Rep

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Determining the contributions of different transporter species to overall cellular transport is fundamental for understanding the physiological regulation of solutes. We calculated the relative activities of Solute Carrier (SLC) transporters using the Michaelis-Menten equation and global fitting to estimate the normalized maximum transport rate for each transporter (Vmax). Data input were the normalized measured uptake of the essential neutral amino acid (AA) L-leucine (Leu) from concentration-dependence assays performed using Xenopus laevis oocytes. Our methodology was verified by calculating Leu and L-phenylalanine (Phe) data in the presence of competitive substrates and/or inhibitors. Among 9 potentially expressed endogenous X. laevis oocyte Leu transporter species, activities of only the uniporters SLC43A2/LAT4 (and/or SLC43A1/LAT3) and the sodium symporter SLC6A19/B0AT1 were required to account for total uptake. Furthermore, Leu and Phe uptake by heterologously expressed human SLC6A14/ATB0,+ and SLC43A2/LAT4 was accurately calculated. This versatile systems biology approach is useful for analyses where the kinetics of each active protein species can be represented by the Hill equation. Furthermore, its applicable even in the absence of protein expression data. It could potentially be applied, for example, to quantify drug transporter activities in target cells to improve specificity.

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Section: Discussionsupporting

confidence: 80%

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

Taslimifar

Oparija

Verrey

et al. 2017

Sci Rep

Self Cite

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“…It is interesting however that glutamine supplementation increased brain arginine and leucine in both genotypes. It is well known that the cellular homeostasis of these two amino acids depends on transporters, namely y + LAT2 (SLC7A6) for arginine, and LAT1 (SLC7A5) for leucine . Since these transporters also transport glutamine, it is tempting to speculate that the diet‐induced increase in systemic glutamine (Table ) interferes with arginine and leucine cellular transport, leading to their intracellular accumulation.…”

Section: Discussionmentioning

confidence: 99%

Maternal glutamine supplementation in murine succinic semialdehyde dehydrogenase deficiency, a disorder of γ‐aminobutyric acid metabolism

Brown

Walters

Schmidt

et al. 2019

J of Inher Metab Disea

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Murine succinic semialdehyde dehydrogenase deficiency (SSADHD) manifests with high concentrations of γ‐aminobutyric acid (GABA) and γ‐hydroxybutyrate (GHB) and low glutamine in the brain. To understand the pathogenic contribution of central glutamine deficiency, we exposed aldh5a1−/− (SSADHD) mice and their genetic controls (aldh5a1+/+) to either a 4% (w/w) glutamine‐containing diet or a glutamine‐free diet from conception until postnatal day 30. Endpoints included brain, liver and blood amino acids, brain GHB, ataxia scores, and open field testing. Glutamine supplementation did not improve aldh5a1−/− brain glutamine deficiency nor brain GABA and GHB. It decreased brain glutamate but did not change the ratio of excitatory (glutamate) to inhibitory (GABA) neurotransmitters. In contrast, glutamine supplementation significantly increased brain arginine (30% for aldh5a1+/+ and 18% for aldh5a1−/− mice), and leucine (12% and 18%). Glutamine deficiency was confirmed in the liver. The test diet increased hepatic glutamate in both genotypes, decreased glutamine in aldh5a1+/+ but not in aldh5a1−/−, but had no effect on GABA. Dried bloodspot analyses showed significantly elevated GABA in mutants (approximately 800% above controls) and decreased glutamate (approximately 25%), but no glutamine difference with controls. Glutamine supplementation did not impact blood GABA but significantly increased glutamine and glutamate in both genotypes indicating systemic exposure to dietary glutamine. Ataxia and pronounced hyperactivity were observed in aldh5a1−/− mice but remained unchanged by the diet intervention. The study suggests that glutamine supplementation improves peripheral but not central glutamine deficiency in experimental SSADHD. Future studies are needed to fully understand the pathogenic role of brain glutamine deficiency in SSADHD.

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“…Unfortunately, the technical demands of interstitial fluid collection limit its reliability. CSF collection is a strong alternative [65,66], because a large volume can be collected rapidly at high purity and the concentration of insulin in the CSF correlates strongly with the amount of insulin in the brain [36,67]. …”

Section: Discussionmentioning

confidence: 99%

Estrogen and insulin transport through the blood-brain barrier

May‐Zhang

Bedel

Shen

et al. 2016

Physiology & Behavior

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The metabolic syndrome is associated with insulin resistance and reduced transport of insulin through the blood-brain barrier (BBB). Reversal of high-fat diet-induced obesity (HFD-DIO) by dietary intervention improves the transport of insulin through the BBB and the sensitivity of insulin in the brain. Although both insulin and estrogen (E2), when given alone, reduce food intake and body weight via the brain, E2 actually renders the brain relatively insensitive to insulin’s catabolic action. The objective of these studies was to determine if E2 influences the ability of insulin to be transported into the brain, since both E2 and insulin receptors are found in BBB endothelial cells. E2 (acute or chronic) was systemically administered to ovariectomized (OVX) female rats and male rats fed a chow or a high-fat diet. Food intake, body weight and other metabolic parameters were assessed along with insulin entry into the cerebrospinal fluid (CSF). Acute E2 treatment in OVX female and male rats reduced body weight and food intake, and chronic E2 treatment prevented or partially reversed high-fat diet-induced obesity. However, none of these conditions increased insulin transport into the CNS; rather, chronic E2 treatment was associated less-effective insulin transport into the CNS relative to weight-matched controls. Thus, the reduction of brain insulin sensitivity by E2 is unlikely to be mediated by increasing the amount of insulin entering the CNS.

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Brain interstitial fluid glutamine homeostasis is controlled by blood–brain barrier SLC7A5/LAT1 amino acid transporter

Cited by 70 publications

References 40 publications

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

Quantifying the relative contributions of different solute carriers to aggregate substrate transport

Maternal glutamine supplementation in murine succinic semialdehyde dehydrogenase deficiency, a disorder of γ‐aminobutyric acid metabolism

Estrogen and insulin transport through the blood-brain barrier

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