The 4F2hc/LAT1 complex transports l-DOPA across the blood–brain barrier

Kageyama, Takashi; Nakamura, Masaru; Matsuo, Akinori; Yamasaki, Yasuomi; Takakura, Yoshinobu; Hashida, Mitsuru; Kanai, Yoshikatsu; Naito, Mikihiko; Tsuruo, Takashi; Minato, Nagahiro; Shimohama, Shun

doi:10.1016/s0006-8993(00)02758-x

Cited by 249 publications

(172 citation statements)

References 36 publications

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“…The immunostaining intensity of LAT1, however, was increased in the kidney sections of CGN rats on day 7, although its subcellular granular pattern in the cytoplasm remained unchanged (Figure 6b, day 7, inset). Positive staining of LAT1 in the capillary endothelial cells of bloodbrain barrier 30,31 further confirmed the specificity of the anti-LAT1 antibody (Figure 6b, control, inset). A previous study showed a predominant expression of LAT2 at the basolateral membrane of proximal tubules.…”

Section: Expression Of Lats In Normal and Crescentic Glomerulisupporting

confidence: 62%

“…25,26 So far, four LATs (LAT1-LAT4) have been identified at the molecular level. LAT1 27 has been found in many malignant cells; 28,29 however, its clear expression in normal tissues has been only reported in the vascular endothelial cells forming the blood-brain barrier 30,31 and syncytiotrophoblastic cells of the placenta. 32 Expression of LAT2 has been shown in the epithelium of kidney proximal tubules and the digestive tract.…”

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confidence: 99%

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Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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Molecular mechanisms and signaling pathways leading to cellular proliferation and lesion formation in the crescentic glomerulonephritis (CGN) remain elusive. In the present study we have explored a potential role of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway and amino acid transporter (LAT) in the pathogenesis of CGN. Immunohistochemistry and western blot analysis of glomeruli isolated from a rat model of CGN revealed that activation of mTORC1 preceded crescent formation in glomerular parietal epithelial cells (PECs) and podocytes. Daily treatment of rats with the mTOR inhibitor everolimus just after induction of CGN was not beneficial and instead led to increased cellular necrosis of PECs. However, daily treatment starting 7 days after the onset of CGN was beneficial and maintained intact glomeruli. Out of three forms of L-type neutral amino acid transporters (LAT1-LAT3) studied here, only LAT2 was found to be upregulated in the PECs and podocytes in advance of the crescent formation as well as in the crescent lesion itself. Cell culture study revealed that plasma membrane expression of LAT2 markedly stimulated mTORC1 signaling pathway, which was significantly abrogated by coexistence of LAT inhibitor. Finally, LAT inhibitor significantly abrogated development of crescent formation of CGN on day 7. Our data suggest that LAT2 may have a pivotal role in the pathogenesis of CGN by activating the mTORC1 pathway in the glomerular epithelial cells. Crescentic glomerulonephritis (CGN) is the most severe form of glomerulonephritis, and if untreated, progresses to endstage renal failure within days or weeks of diagnosis. Despite different etiologies and clinical manifestations among patients with CGN, there is a common glomerular pathology characterized by the disruption of glomerular basement membrane (GBM), followed by the flow of plasma proteins and inflammatory cells into the Bowman's space. 1 Several studies suggest that proliferating glomerular epithelial cells and accumulation of infiltrated macrophages are the main components of the cellular crescents. 2-6 Recent reports have further revealed that the cellular crescent lesions in CGN consist of podocytes in addition to glomerular parietal epithelial cells (PECs) and macrophages. [7][8][9] It is increasingly evident that proinflammatory cytokines and growth hormones released by proliferating cells in the glomerulus are involved in the pathogenesis of crescent formation. [10][11][12][13] These factors stimulate the p38 mitogen-activated protein kinase (MAPK) pathway, resulting in the production of inflammatory mediators. [14][15][16] The involvement of the MAPK pathway in the pathogenesis of CGN was first reported by Bokemeyer et al, 17 who demonstrated a rapid and sustained activation of extracellular signal-regulated kinase in the glomeruli isolated from rat model of anti-GBM nephritis. A further study demonstrated that both podocytes and the crescent lesion are the main source of p38MAPK activation, although additional signaling path...

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Section: Expression Of Lats In Normal and Crescentic Glomerulisupporting

confidence: 62%

mentioning

confidence: 99%

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Kurayama

Ito

Nishibori

et al. 2011

Laboratory Investigation

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“…L-DOPA is used in the treatment of Parkinson Disease and is a dopamine precursor that is transported across the BBB via the LAT1 carrier. 55 Alternatively, drugs might be conjugated to substances that normally cross the BBB by carrier mediated processes. Further, the presence of endogenous receptors with specific ligands triggering BBB crossing mechanisms, such as the insulin receptor or the TfR, enables the engineering of peptides that attached to compounds or drugs mimic these ligands.…”

Section: Mechanism Of Bbb Crossing By Endogenous Substancesmentioning

confidence: 99%

Nanoparticle transport across the blood brain barrier

et al. 2016

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While the role of the blood-brain barrier (BBB) is increasingly recognized in the (development of treatments targeting neurodegenerative disorders, to date, few strategies exist that enable drug delivery of non-BBB crossing molecules directly to their site of action, the brain. However, the recent advent of Nanomedicines may provide a potent tool to implement CNS targeted delivery of active compounds. Approaches for BBB crossing are deeply investigated in relation to the pathology: among the main important diseases of the CNS, this review focuses on the application of nanomedicines to neurodegenerative disorders (Alzheimer, Parkinson and Huntington's Disease) and to other brain pathologies as epilepsy, infectious diseases, multiple sclerosis, lysosomal storage disorders, strokes.

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“…Not only nutrients but also several drugs are translocated into the brain across the BBB. For example, MCT1 and LAT1 transport L-dopa (Gomes and Soares-da-Silva, 1999;Kageyama et al, 2000). Organic anion transporter 3 (OAT3, SLC22A8) and/or organic anion transport polypeptide (Oatp1a4, Slco1a4) mediate the efflux transport of endogenous metabolites (Mori et al, 2003) and several anionic drugs, such as digoxin (Kusuhara et al, 2003), simvastatin (Tsuji, 2005), and 6-mercaptopurine (Deguchi et al, 2000;Mori et al, 2004) across the BBB.…”

mentioning

confidence: 99%

Involvement of the Pyrilamine Transporter, a Putative Organic Cation Transporter, in Blood-Brain Barrier Transport of Oxycodone

Okura¹,

Hattori²,

Takano³

et al. 2008

Drug Metab Dispos

152

173

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ABSTRACT:The purpose of this study was to characterize blood-brain barrier (BBB) transport of oxycodone, a cationic opioid agonist, via the pyrilamine transporter, a putative organic cation transporter, using conditionally immortalized rat brain capillary endothelial cells (TR-BBB13). Oxycodone and [ 3 H]pyrilamine were both transported into TR-BBB13 cells in a temperature-and concentration-dependent manner with K m values of 89 and 28 M, respectively. The initial uptake of oxycodone was significantly enhanced by preloading with pyrilamine and vice versa. Furthermore, mutual uptake inhibition by oxycodone and pyrilamine suggests that a common mechanism is involved in their transport. Transport of both substrates was inhibited by type II cations (quinidine, verapamil, and amantadine), but not by classic organic cation transporter (OCT) substrates and/or inhibitors (tetraethylammonium, 1-methyl-4-phenylpyridinium, and corticosterone), substrates of OCTN1 (ergothioneine) and OCTN2 (L-carnitine), or organic anions. The transport was inhibited by metabolic inhibitors (rotenone and sodium azide) but was insensitive to extracellular sodium and membrane potential for both substrates. Furthermore, the transport of both substrates was increased at alkaline extracellular pH and decreased in the presence of a protonophore (carbonyl cyanide-ptrifluoromethoxyphenylhydrazone). Intracellular acidification induced with ammonium chloride enhanced the uptakes, suggesting that the transport is driven by an oppositely directed proton gradient. The brain uptake of oxycodone measured by in situ rat brain perfusion was increased in alkaline perfusate and was significantly inhibited by pyrilamine. These results suggest that blood-brain barrier transport of oxycodone is at least partly mediated by a common transporter with pyrilamine, and this transporter is an energy-dependent, proton-coupled antiporter.

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The 4F2hc/LAT1 complex transports l-DOPA across the blood–brain barrier

Cited by 249 publications

References 36 publications

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Role of amino acid transporter LAT2 in the activation of mTORC1 pathway and the pathogenesis of crescentic glomerulonephritis

Nanoparticle transport across the blood brain barrier

Involvement of the Pyrilamine Transporter, a Putative Organic Cation Transporter, in Blood-Brain Barrier Transport of Oxycodone

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