Acute Insult of Ammonia Leads to Calcium-dependent Glutamate Release from Cultured Astrocytes, an Effect of pH

Rose, Christopher F.; Kresse, Wolfgang; Kettenmann, Helmut

doi:10.1074/jbc.m412448200

Cited by 104 publications

(94 citation statements)

References 45 publications

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“…2). Similar results are observed when other weak bases are applied to cultured cell preparations such as trimethylamine (Rose et al 2005). However, the ammonia-induced transient increase in [pH]i recovers towards baseline since NH4 + (>98%) is capable of crossing cell membranes (at a slower rate than NH3 diffusion) through different channels and transporters (see above).…”

Section: Phsupporting

confidence: 61%

Identifying the direct effects of ammonia on the brain

2008

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Elevated concentrations of ammonia in the brain as a result of hyperammonemia leads to cerebral dysfunction involving a spectrum of neuropsychiatric and neurological symptoms (impaired memory, shortened attention span, sleep-wake inversions, brain edema, intracranial hypertension, seizures, ataxia and coma). Many studies have demonstrated ammonia as a major player involved in the neuropathophysiology associated with liver failure and inherited urea cycle enzyme disorders. Ammonia in solution is composed of a gas (NH3) and an ionic (NH4 + ) component which are both capable of crossing plasma membranes through diffusion, channels and transport mechanisms and as a result have a direct effect on pH. Furthermore, NH4 + has similar properties as K + and, therefore, competes with K + on K + transporters and channels resulting in a direct effect on membrane potential. Ammonia is also a product as well as a substrate for many different biochemical reactions and consequently, an increase in brain ammonia accompanies disturbances in cerebral metabolism. These direct effects of elevated ammonia concentrations on the brain will lead to a cascade of secondary effects and encephalopathy.

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Section: Phsupporting

confidence: 61%

Identifying the direct effects of ammonia on the brain

2008

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“…Additionally, SN2 activity is regulated by pH, having its activity decreased with lower pH, partially due to an action at the histidine residues found in the transporter (Baird et al, 2006). During HE, it has been described that ammonia leads to intracellular astrocytic alkalinization, as demonstrated in both cell cultures and astrocytes from portacaval-shunted rats (Rose et al, 2005;Swain et al, 1991). Therefore, an increase in pH might interfere with glutamine transporter activity in the astrocytic compartment.…”

Section: Discussionmentioning

confidence: 99%

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Leke

Escobar

Rao

et al. 2015

Neurochemistry International

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Rama Rao, Kakulavarapu V.; Silveira, Themis Reverbel; Norenberg, Michael D.; and Schousboe, Arne, "Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy" (2015 Keywords:Chronic hepatic encephalopathy Glutamine transporters Glutamine GABA A B S T R A C THepatic encephalopathy (HE) is a neuropsychiatric disorder that occurs due to acute and chronic liver diseases, the hallmark of which is the increased levels of ammonia and subsequent alterations in glutamine synthesis, i.e. conditions associated with the pathophysiology of HE. Under physiological conditions, glutamine is fundamental for replenishment of the neurotransmitter pools of glutamate and GABA. The different isoforms of glutamine transporters play an important role in the transfer of this amino acid between astrocytes and neurons. A disturbance in the GABA biosynthetic pathways has been described in bile duct ligated (BDL) rats, a well characterized model of chronic HE. Considering that glutamine is important for GABA biosynthesis, altered glutamine transport and the subsequent glutamate/GABA-glutamine cycle efficacy might influence these pathways. Given this potential outcome, the aim of the present study was to investigate whether the expression of the glutamine transporters SAT1, SAT2, SN1 and SN2 would be affected in chronic HE. We verified that mRNA expression of the neuronal glutamine transporters SAT1 and SAT2 was found unaltered in the cerebral cortex of BDL rats. Similarly, no changes were found in the mRNA level for the astrocytic transporter SN1, whereas the gene expression of SN2 was increased by two-fold in animals with chronic HE. However, SN2 protein immuno-reactivity did not correspond with the increase in gene transcription since it remained unaltered. These data indicate that the expression of the glutamine transporter isoforms is unchanged during chronic HE, and thus likely not to participate in the pathological mechanisms related to the imbalance in the GABAergic neurotransmitter system observed in this neurologic condition.

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“…Increases in extracellular glutamate concentration may result from increased glutamate release or reduced glutamate uptake, and experimental evidence exists supporting both mechanisms [7]. Interestingly, a number of studies reported that NH 4 + / NH 3 evokes glutamate release from astrocytes in a Ca 2+ dependent manner ( [8,2,7]; see below). In addition, reductions in glutamate uptake were observed in animal models and in cultured astrocytes following chronic NH 4 + /NH 3 exposure and were attributed to reductions in the expression of glial glutamate transporters (see [7]; Box.…”

Section: He and Glutamate Transmissionmentioning

confidence: 99%

“…sodium, potassium and chloride). Thus, in addition to pH changes, NH 4 + /NH 3 -evoked changes in the intracellular concentrations of other ions may contribute to the toxic effects of NH 4 + /NH 3 in turn mediated Ca 2+ -dependent release of glutamate from cultured cortical astrocytes ( [8]; see also [2]). …”

Section: The Effects Of Ammonium-evoked Changes In Intracellular Phmentioning

confidence: 99%

Intracellular ion homeostasis

Kelly

Rose

2010

E-Neuroforum

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The term hepatic encephalopathy (HE) refers to a number of potentially reversible neurological deficits resulting from liver dysfunction [11]. Chronic HE, as seen in alcohol-induced liver cirrhosis, is characterised by personality changes, altered mood and diminished intellectual ability.Acute HE occurs following acute liver failure, resulting from for example viral hepatitis and paracetamol intoxication, is associated with neurological deficits ranging from impairment of fine motor skill to muscle spasticity [uncoordinated movements (ataxia)], and finally impaired consciousness and coma. In most patients with acute liver failure, cerebral oedema ensues and is the predominate cause of death (80-90% mortality rate). The only effective treatment presently available for the cerebral oedema in ALF is an emergency liver transplantation. Ammonium (NH 4 + and ammonia (NH 3 ) are considered the primary toxins responsible for the functional deficits observed in HE, the treatment of which is based primarily on reducing blood and brain NH 4 + /NH 3 concentrations. The arterial concentration of NH 4 + /NH 3 in HE patients and HE animal models is increased, and predicts the severity of the symptoms [1]. In the portocaval anastomosis animal model of chronic HE, a surgically placed shunt allows blood from the intestine to bypass the liver (unfiltered) and enter the main circulatory system, increasing arterial NH 4 + /NH 3 concentrations. Under physiological conditions, NH 4 + /NH 3 concentrations in arterial blood are 50-100 µmol/l; this level doubles in chronic HE, while in the central nervous system it rises three-to four-fold. In contrast, at the coma stage of acute HE the NH 4 + / NH 3 concentrations in the CNS of animal models reach 1-5 mM [1]. Ammonium's central role Astrocytes and HERecent evidence suggests that astrocytes are an important cellular site of action for NH 4 + /NH 3 in the pathology of HE (see [1,3]). In particular, astrocytic swelling observed in animal models following exposure to NH 4 + /NH 3 likely contributes to the brain oedema, a frequent cause of mortality in acute HE. In addition, neuronal loss is rarely observed in the mature brain following NH 4 + /NH 3 exposure [1], and the neuropsychiatric symptoms characteristic of acute or chronic HE are reversible following recovery of hepatic function [11].The greater sensitivity of astrocytes to NH 4 + /NH 3 compared with neurones likely reflects the mechanism of NH 4 + cellular influx (see below) and/or astrocyte specific pathway(s) particularly sensitive to NH 4 + /NH 3 . In regard to the latter, astrocytes are the cellular site for NH 4 + detoxification in the CNS. Ammonium is detoxified in the CNS by the enzyme glutamine synthetase, which is located almost exclusively in astrocytes. In this process, the conversion of glutamate to glutamine incorporates ammonium, glutamine is converted back into glutamate after neuronal uptake (glutamate-glutamine shuttle; see Box. 1). Furthermore, increases in cellular glutamine concentrations are a consistent hallm...

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Acute Insult of Ammonia Leads to Calcium-dependent Glutamate Release from Cultured Astrocytes, an Effect of pH

Cited by 104 publications

References 45 publications

Identifying the direct effects of ammonia on the brain

Identifying the direct effects of ammonia on the brain

Expression of glutamine transporter isoforms in cerebral cortex of rats with chronic hepatic encephalopathy

Intracellular ion homeostasis

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