Dysregulation of Astrocytic Glutamine Transport in Acute Hyperammonemic Brain Edema

Zielińska, Magdalena; Albrecht, Jan; Popek, Mariusz

doi:10.3389/fnins.2022.874750

Cited by 9 publications

(5 citation statements)

References 211 publications

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“…Astrocytes are the exclusive possessors of glutamine synthetase in the brain, 137 which makes them the main target for ammonium. Most of ammonium entering the brain is converted to glutamine, which causes glutaminosis 359 and effectively lowers brain parenchymal ammonium concentrations, but which also maintains the concentration gradient and favours additional entry of ammonium from the blood to the brain. 360 At the cellular level, excess of ammonium mainly affects astrocytes with neuronal injury being secondary, resulting mainly from failure of astrocytic homoeostatic cascades and oedema.…”

Section: Astrocytes As Main Target Of Toxic Encephalopathiesmentioning

confidence: 99%

Astrocytes in human central nervous system diseases: a frontier for new therapies

Verkhratsky,

Butt,

et al. 2023

Sig Transduct Target Ther

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Astroglia are a broad class of neural parenchymal cells primarily dedicated to homoeostasis and defence of the central nervous system (CNS). Astroglia contribute to the pathophysiology of all neurological and neuropsychiatric disorders in ways that can be either beneficial or detrimental to disorder outcome. Pathophysiological changes in astroglia can be primary or secondary and can result in gain or loss of functions. Astroglia respond to external, non-cell autonomous signals associated with any form of CNS pathology by undergoing complex and variable changes in their structure, molecular expression, and function. In addition, internally driven, cell autonomous changes of astroglial innate properties can lead to CNS pathologies. Astroglial pathophysiology is complex, with different pathophysiological cell states and cell phenotypes that are context-specific and vary with disorder, disorder-stage, comorbidities, age, and sex. Here, we classify astroglial pathophysiology into (i) reactive astrogliosis, (ii) astroglial atrophy with loss of function, (iii) astroglial degeneration and death, and (iv) astrocytopathies characterised by aberrant forms that drive disease. We review astroglial pathophysiology across the spectrum of human CNS diseases and disorders, including neurotrauma, stroke, neuroinfection, autoimmune attack and epilepsy, as well as neurodevelopmental, neurodegenerative, metabolic and neuropsychiatric disorders. Characterising cellular and molecular mechanisms of astroglial pathophysiology represents a new frontier to identify novel therapeutic strategies.

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Section: Astrocytes As Main Target Of Toxic Encephalopathiesmentioning

confidence: 99%

Astrocytes in human central nervous system diseases: a frontier for new therapies

Verkhratsky,

Butt,

et al. 2023

Sig Transduct Target Ther

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“…They transport glutamine into synapses while transporting Na + in the same direction and H + in the opposite direction 43,45 . In vitro studies of primary astrocyte cultures have shown that system N contributes between 10% and 50% of the total glutamine transport capacity 46 . Among system N transporters, SLC38A3 is the major transporter for glutamine release in astrocytes, whereas SLC38A5 has a relatively high affinity for serine 46 .…”

Section: Glutamate–glutamine Cyclementioning

confidence: 99%

“… 43 , 45 In vitro studies of primary astrocyte cultures have shown that system N contributes between 10% and 50% of the total glutamine transport capacity. 46 Among system N transporters, SLC38A3 is the major transporter for glutamine release in astrocytes, whereas SLC38A5 has a relatively high affinity for serine. 46 Studies demonstrate that the Km values for glutamine efflux facilitated by SLC38A3 and SLC38A5 are 1.57 and 1.2 mM, respectively.…”

Section: Glutamate–glutamine Cyclementioning

confidence: 99%

“… 46 Among system N transporters, SLC38A3 is the major transporter for glutamine release in astrocytes, whereas SLC38A5 has a relatively high affinity for serine. 46 Studies demonstrate that the Km values for glutamine efflux facilitated by SLC38A3 and SLC38A5 are 1.57 and 1.2 mM, respectively. 47 , 48 The excretion of glutamine from astrocytes is not only to provide a precursor of neurotransmitters for neurons but also to prevent the accumulation of glutamine from causing damage to astrocytes.…”

Section: Glutamate–glutamine Cyclementioning

confidence: 99%

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The role of glutamate and glutamine metabolism and related transporters in nerve cells

Zhang,

Hua,

2024

CNS Neurosci Ther

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BackgroundGlutamate and glutamine are the most abundant amino acids in the blood and play a crucial role in cell survival in the nervous system. Various transporters found in cell and mitochondrial membranes, such as the solute carriers (SLCs) superfamily, are responsible for maintaining the balance of glutamate and glutamine in the synaptic cleft and within cells. This balance affects the metabolism of glutamate and glutamine as non‐essential amino acids.AimsThis review aims to provide an overview of the transporters and enzymes associated with glutamate and glutamine in neuronal cells.DiscussionWe delve into the function of glutamate and glutamine in the nervous system by discussing the transporters involved in the glutamate‐glutamine cycle and the key enzymes responsible for their mutual conversion. Additionally, we highlight the role of glutamate and glutamine as carbon and nitrogen donors, as well as their significance as precursors for the synthesis of reduced glutathione (GSH).ConclusionGlutamate and glutamine play a crucial role in the brain due to their special effects. It is essential to focus on understanding glutamate and glutamine metabolism to comprehend the physiological behavior of nerve cells and to treat nervous system disorders and cancer.

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“…Ammonium circulating in excess enters the brain, where it is detoxified and converted to glutamine by astrocyte resident glutamine synthetase (Brusilow et al, 2010;Cooper et al, 1979). Pathological increase of glutamine in the brain leads to a multifaceted homeostatic imbalance (Zielińska et al, 2022), which is clinically manifested by delirium, hallucinations, acute psychosis, and, in a terminal phase, coma leading to death (Weissenborn, 2019). In HE astrocytes undergo multiple morphological changes (Albrecht & Jones, 1999;Gelpi et al, 2020) ranging from reactive astrogliosis, swelling (that contributes to brain oedema), and the emergence of disease-specific aberrant astrocytes known as Alzheimer type II astrocytes, the term introduced in 1942 (Waggoner & Malamud, 1942).…”

Section: Introductionmentioning

confidence: 99%

Aberrant remodelling of astrocytic architecture in acute hepatic encephalopathy: complexity of oedematic atrophic astrocytes

Popek,

Obara-Michlewska,

Szewczyk

et al. 2024

Preprint

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Hepatic encephalopathy (HE) following acute liver failure (ALF) is a primary toxic astrocytopathy, although in-depth characterisation of underlying pathogenesis is far from complete. Among the multitude of astrocyte-specific proteins guiding brain functionality, plasmalemma-cytoskeletal linker ezrin, actin-binding protein profilin-1, and water channel aquaporin 4 (AQP4) contribute to astrocytic morphological plasticity through regulation of cell shape, volume, complexity of primary and terminal processes, and positioning astrocytes against other CNS constituents. Changes in these proteins might contribute to the brain oedema and astrocytic morphological remodelling in the HE. Using transmission electron microscopy, confocal fluorescent microscopy, and 3D reconstruction, we found complex morphological alterations of cortical astrocytes in mice with azoxymethane-induced ALF. Astrocytic primary branches demonstrated hypertrophy, whereas terminal leaflets showed atrophy quantified by the reduced area occupied by astrocytes, decreased number and the length of leaflets, decreased leaflets volume fraction, and altered astrocyte-to-neurone landscape. These morphological changes correlat with decreased expression of AQP4, phosphorylated leaflet-associated ezrin, and the actin dynamics regulator, profilin 1, suggesting the contribution of these proteins to astrocytic pathological remodelling. Pathological changes in astrocytes develop in parallel, and are likely causally linked to, the HE-linked neurological decline, manifested by a reduction in electroencephalography power and by excessive glutamate in the brain microdialysates.Abstract FigureGraphical abstract:Hepatic encephalopathy is associated with astrocyte remodelling manifested by swelling of the soma and primary branches together with atrophy of distal branches and leaflets; the latter retract from synapses thus affecting neurotransmission and contribute to the reduced neuronal activity. Astrocyte remodelling was linked to (and probably instigated by) a decrease of plasmalemma-cytoskeleton linker phosphorylated ezrin (Phos-ezrin), actin modulator profilin-1 (PFN1) and water channel aquaporin 4 (AQP4).

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Dysregulation of Astrocytic Glutamine Transport in Acute Hyperammonemic Brain Edema

Cited by 9 publications

References 211 publications

Astrocytes in human central nervous system diseases: a frontier for new therapies

Astrocytes in human central nervous system diseases: a frontier for new therapies

The role of glutamate and glutamine metabolism and related transporters in nerve cells

Aberrant remodelling of astrocytic architecture in acute hepatic encephalopathy: complexity of oedematic atrophic astrocytes

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