Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y+LAT2 in rat cerebral cortex: Implications for the nitric oxide/cGMP pathway

Zielińska, Magdalena; Ruszkiewicz, Joanna A.; Hilgier, Wojciech; Fręśko, Inez

doi:10.1016/j.neuint.2010.11.015

Cited by 29 publications

(31 citation statements)

References 44 publications

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“…A hypothesis that such an interaction may occur is supported by the observation that, Gln infusion in the absence of hyperammonemia impairs cerebrovascular CO 2 reactivity, most likely by reducing Arg availability and NO synthesis, because co-infusion of Arg counteracts the effect caused by glutamine (Okada et al 2000). Consistent with the role of Arg/Gln exchange at the BBB, our preliminary data indicate that ammonia increases the expression of the y + LAT2 transporter in a cerebral capillary endothelial cell line (manuscript in preparation), as it does in the brain in the course of HA in situ (Zielińska et al 2011). …”

Section: Transcellular Passage Of Different Molecules Across the Endosupporting

confidence: 78%

“…The effects of HE on Arg transport are also likely to be mediated by Gln, which accumulates intracerebrally in consequence of increased ammonia influx (Cooper and Plum 1987), overloading different cellular and subcellular compartments of the CNS (Albrecht 2010). It has been shown that Gln added exogenously reduces NO generation in the brain by inhibiting Arg transport via the Arg/Gln exchanger, y + LAT2, and that this effect is potentiated when ammonia is infused directly to the brain (Hilgier et al 2009), or accumulates in there during HE (Zielińska et al 2011). If the above mechanism operates not only in the CNS cells but also in the cerebral capillary endothelial cells forming the BBB, enhanced Gln accumulation would modulate Arg transport in these cells.…”

Section: Transcellular Passage Of Different Molecules Across the Endomentioning

confidence: 99%

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Alterations of Blood Brain Barrier Function in Hyperammonemia: An Overview

Skowrońska

Albrecht

2011

Neurotox Res

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Ammonia is a neurotoxin involved in the pathogenesis of neurological conditions associated with hyperammonemia, including hepatic encephalopathy, a condition associated with acute—(ALF) or chronic liver failure. This article reviews evidence that apart from directly affecting the metabolism and function of the central nervous system cells, ammonia influences the passage of different molecules across the blood brain barrier (BBB). A brief description is provided of the tight junctions, which couple adjacent cerebral capillary endothelial cells to each other to form the barrier. Ammonia modulates the transcellular passage of low-to medium-size molecules, by affecting their carriers located at the BBB. Ammonia induces interrelated aberrations of the transport of the large neutral amino acids and aromatic amino acids (AAA), whose influx is augmented by exchange with glutamine produced in the course of ammonia detoxification, and maybe also modulated by the extracellularly acting gamma-glutamyl moiety transferring enzyme, gamma-glutamyl-transpeptidase. Impaired AAA transport affects neurotransmission by altering intracerebral synthesis of catecholamines (serotonin and dopamine), and producing “false neurotransmitters” (octopamine and phenylethylamine). Ammonia also modulates BBB transport of the cationic amino acids: the nitric oxide precursor, arginine, and ornithine, which is an ammonia trap, and affects the transport of energy metabolites glucose and creatine. Moreover, ammonia acting either directly or in synergy with liver injury-derived inflammatory cytokines also evokes subtle increases of the transcellular passage of molecules of different size (BBB “leakage”), which appears to be responsible for the vasogenic component of cerebral edema associated with ALF.

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Section: Transcellular Passage Of Different Molecules Across the Endosupporting

confidence: 78%

Section: Transcellular Passage Of Different Molecules Across the Endomentioning

confidence: 99%

Alterations of Blood Brain Barrier Function in Hyperammonemia: An Overview

Skowrońska

Albrecht

2011

Neurotox Res

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“…However, recent in vitro study on human embryonic kidney (HEK293) cells suggested involvement in ADMA redistribution of other transporters, such as organic cation transporter 2 and multidrug and toxin extrusion protein 1 (Strobel et al, 2012). Of note, y + LAT2 transporter plays an important role in depletion of surplus intracellular ADMA, which may lead to NOS inhibition (Closs et al, 2012), and our earlier studies indeed revealed substantial changes of the y + LAT2 transporter expression and activity in the brain of rats with TAA-induced ALF (Zieliń ska et al, 2011). Uptake or efflux transporter function, which is required by positively charged ADMA to pass cellular membranes, may be modified by endogenous or exogenously added substances and may affect elimination and cerebral concentrations of ADMA: His is likely to have acted along this route.…”

Section: Article In Presssupporting

confidence: 50%

The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: Modulation by histidine

Milewski

Hilgier

Albrecht

et al. 2015

Neurochemistry International

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“…The y + L system is represented by 4F2hc/y + LAT1 and 4F2hc/y + LAT2 transporters, which in addition to cationic amino acids accept neutral amino acids; the transport of the latter is coupled to Na + [24]. Of these two transporters, the brain expresses only y + LAT2 [25, 26], which appears to abound in astrocytes and as such is well suited for catalyzing Gln/Arg exchange in these cells [27]. …”

Section: Gln Transport In the Cnsmentioning

confidence: 99%

“…Further details were as described in Ref. [27]. Values in each group are mean ± SD for n = 8; * p < 0.05; T test.…”

Section: Effects Of He On Gln Transport In the Brain And Expression Omentioning

confidence: 99%

Roles of Changes in Active Glutamine Transport in Brain Edema Development During Hepatic Encephalopathy: An Emerging Concept

Zielińska

Popek

2013

Neurochem Res

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Excessive glutamine (Gln) synthesis in ammonia-overloaded astrocytes contributes to astrocytic swelling and brain edema, the major complication of hepatic encephalopathy (HE). Much of the newly formed Gln is believed to enter mitochondria, where it is recycled to ammonia, which causes mitochondrial dysfunction (a “Trojan horse” mode of action). A portion of Gln may increase osmotic pressure in astrocytes and the interstitial space, directly and independently contributing to brain tissue swelling. Here we discuss the possibility that altered functioning of Gln transport proteins located in the cellular or mitochondrial membranes, modulates the effects of increased Gln synthesis. Accumulation of excess Gln in mitochondria involves a carrier-mediated transport which is activated by ammonia. Studies on the expression of the cell membrane N-system transporters SN1 (SNAT3) and SN2 (SNAT5), which mediate Gln efflux from astrocytes rendered HE model-dependent effects. HE lowered the expression of SN1 at the RNA and protein level in the cerebral cortex (cc) in the thioacetamide (TAA) model of HE and the effect paralleled induction of cerebral cortical edema. Neither SN1 nor SN2 expression was affected by simple hyperammonemia, which produces no cc edema. TAA-induced HE is also associated with decreased expression of mRNA coding for the system A carriers SAT1 and SAT2, which stimulate Gln influx to neurons. Taken together, changes in the expression of Gln transporters during HE appear to favor retention of Gln in astrocytes and/or the interstitial space of the brain. HE may also affect arginine (Arg)/Gln exchange across the astrocytic cell membrane due to changes in the expression of the hybrid Arg/Gln transporter y+LAT2. Gln export from brain across the blood–brain barrier may be stimulated by HE via its increased exchange with peripheral tryptophan.

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Hyperammonemia increases the expression and activity of the glutamine/arginine transporter y+LAT2 in rat cerebral cortex: Implications for the nitric oxide/cGMP pathway

Cited by 29 publications

References 44 publications

Alterations of Blood Brain Barrier Function in Hyperammonemia: An Overview

Alterations of Blood Brain Barrier Function in Hyperammonemia: An Overview

The dimethylarginine (ADMA)/nitric oxide pathway in the brain and periphery of rats with thioacetamide-induced acute liver failure: Modulation by histidine

Roles of Changes in Active Glutamine Transport in Brain Edema Development During Hepatic Encephalopathy: An Emerging Concept

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