β-Alanine and l-histidine transport across the inner blood-retinal barrier: Potential involvement in l-carnosine supply

Usui, Takuya; Kubo, Yoshiyuki; Akanuma, Shin Ichi; Hosoya, Ken

doi:10.1016/j.exer.2013.06.002

Cited by 29 publications

(20 citation statements)

References 51 publications

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“…B 0 AT2, and NTT4) [19–21], Na + -independent amino acid transporters (e.g. LATs and CATs, belong to SLC7 family) [17,18], and the peptide/histidine transporter PHT1 [4,22]. Among the amino acid transporters tested in the present study, NTT4, SNAT1 and SNAT3 showed extensive transcription.…”

Section: Discussionmentioning

confidence: 78%

“…Studies on the transport of L-His in brain would extend our understanding of neuropeptide regulation, histamine homeostasis, and potential targets for drug delivery to neuronal and non-neuronal cells. In the central nervous system (CNS), major transporters for L-His include the Na + -coupled neutral amino acid transporters (e.g., SNATs, which belong to the SLC38 family) [15,16], Na + -independent amino acid transporters (e.g., LATs and CATs, which belong to the SLC7 family) [17,18], some members of the Na + -and Cl − -dependent neurotransmitter transporter family (e.g., B 0 AT2 and NTT4, which belong to the SLC6 family) [19–21], as well as the peptide/histidine transporters (e.g., PHT1 and PHT2, which belong to the SLC15 family) [4,22]. …”

Section: Introductionmentioning

confidence: 99%

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A novel role for PHT1 in the disposition of l -histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice

Wang

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et al. 2017

Biochemical Pharmacology

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PHT1 (SLC15A4) is responsible for translocating L-histidine (L-His), di/tripeptides and peptide-like drugs across biological membranes. Previous studies have indicated that PHT1 is located in brain parenchyma, however, its role and significance in brain along with effect on the biodistribution of substrates is unknown. In this study, adult gender-matched Pht1-competent (wildtype) and Pht1-deficient (null) mice were used to investigate the effect of PHT1 on L-His brain disposition via in vitro slice and in vivo pharmacokinetic approaches. We also evaluated the serum clinical chemistry and expression levels of select transporters and enzymes in the two genotypes. No significant differences were observed between genotypes in serum chemistry, body weight, viability and fertility. PCR analyses indicated that Pept2 had a compensatory up-regulation in Pht1 null mice (about 2-fold) as compared to wildtype animals, which was consistent in different brain regions and confirmed by immunoblots. The uptake of L-His was reduced in brain slices by 50% during PHT1 ablation. The L-amino acid transporters accounted for 30% of the uptake, and passive (other) pathways for 20% of the uptake. During the in vivo pharmacokinetic studies, plasma concentration-time profiles of L-His were comparable between the two genotypes after intravenous administration. Still, biodistribution studies revealed that, when sampled 5 min after dosing, L-His values were 28–48% lower in Pht1 null mice, as compared to wildtype animals, in brain parenchyma but not cerebrospinal fluid. These findings suggest that PHT1 may play an important role in histidine transport in brain, and resultant effects on histidine/histamine homeostasis and neuropeptide regulation.

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Section: Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

A novel role for PHT1 in the disposition of l -histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice

Wang

Keep

et al. 2017

Biochemical Pharmacology

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“…Furthermore, the contribution of TauT as the influx transporter of β-Ala across the inner BRB has recently been reported in the enzymatic synthesis of L-carnosine in the retina, showing a new insight into peptide supply to the retina. 80) In addition, the involvement of GAT2 has been also suggested in the uptake of GAA in the liver, which contributes to the biosynthesis of creatine that plays a role in the storage and transmission of phosphate-bound energy.…”

Section: Resultsmentioning

confidence: 99%

Impact of SLC6A Transporters in Physiological Taurine Transport at the Blood–Retinal Barrier and in the Liver

Kubo

Akanuma

Hosoya

2016

Biological & Pharmaceutical Bulletin

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Cumulative studies showed that taurine (2-aminoethanesulfonic acid) contributes to a variety of physiological events. Transport study suggested the cellular taurine transport in an Na -and Cl -dependent manner, and the several members of SLC6A family have been shown as taurine transporter. At the inner blood-retinal barrier (BRB), taurine transporter (TauT/SLC6A) is involved in the transport of taurine to the retina from the circulating blood. The involvement of TauT is also suggested in γ-aminobutyric acid (GABA) transport at the inner BRB, and its role is assumed in the elimination of GABA from the retinal interstitial fluid. In the retina, taurine is thought to be a major organic osmolyte, and its influx and efflux through TauT and volume-sensitive organic osmolyte and anion channel (VSOAC) in Müller cells regulate the osmolarity in the retinal microenvironment to maintain a healthy retina. In the liver, hepatocytes take up taurine via GABA transporter 2 (GAT2/SLC6A13, the orthologue of mouse GAT3) expressed at the sinusoidal membrane of periportal hepatocytes, contributing to the metabolism of bile acid. Site-directed mutagenesis study suggests amino acid residues that are crucial in the recognition of substrates by GATs and TauT. The evidence suggests the physiological impact of taurine transporters in tissues.

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“…A saturated taurine uptake in HaCaT keratinocytes, renal LLC‐PK 1 epithel cells, and intestinal CaCo‐2 cells was estimated even if cells were treated with micromolar taurine concentrations. Furthermore, other ß‐ amino acids, such as ß‐alanine and γ‐aminobutyric acid, are substrates for TAUT and in turn antagonists of the taurine transport . Grafe et al.…”

Section: Introduction To Taurinementioning

confidence: 99%

Taurine: A Regulator of Cellular Redox Homeostasis and Skeletal Muscle Function

Seidel

Huebbe

Rimbach

2018

Molecular Nutrition Food Res

124

118

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Taurine is a nonproteinogenic ß-aminosulfonic acid. Important dietary sources of taurine are fish and seafood. Taurine interacts with ion channels, stabilizes membranes, and regulates the cell volume. These actions confirm its high concentrations in excitable tissues like retina, neurons, and muscles. Retinal degeneration, cardiomyopathy, as well as skeletal muscle malfunction are evident in taurine-deficient phenotypes. There is evidence that taurine counteracts lipid peroxidation and increases cellular antioxidant defense in response to inflammation. In activated neutrophils, taurine reacts with hypochloric acid to form taurine chloramine, which triggers the Kelch-like ECH-associated protein 1-nuclear factor E2-related factor 1 (Keap1-Nrf2) pathway. Consequently, Nrf2 target genes, such as heme oxygenase-1 and catalase, are induced. Furthermore, taurine may prevent an overload of reactive oxygen species (ROS) directly by an inhibition of ROS generation within the respiratory chain. Taurine affects mitochondrial bioenergetics and taurine-deficient mice exhibit an impaired exercise performance. Moreover, some studies demonstrate that taurine enhances the glycogen repletion in the postexercise recovery phase. In the case of taurine deficiency, many studies observed a phenotype known in muscle senescence and skeletal muscle disorders. Overall, taurine plays an important role in cellular redox homeostasis and skeletal muscle function.

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β-Alanine and l-histidine transport across the inner blood-retinal barrier: Potential involvement in l-carnosine supply

Cited by 29 publications

References 51 publications

A novel role for PHT1 in the disposition of l -histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice

A novel role for PHT1 in the disposition of l -histidine in brain: In vitro slice and in vivo pharmacokinetic studies in wildtype and Pht1 null mice

Impact of SLC6A Transporters in Physiological Taurine Transport at the Blood–Retinal Barrier and in the Liver

Taurine: A Regulator of Cellular Redox Homeostasis and Skeletal Muscle Function

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