Effects of ammonia on high affinity glutamate uptake and glutamate transporter EAAT3 expression in cultured rat cerebellar granule cells

Chan, Helen; Zwingmann, Claudia; Pannunzio, Marc; Butterworth, Roger F.

doi:10.1016/s0197-0186(02)00215-2

Cited by 25 publications

(15 citation statements)

References 42 publications

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“…1). Similar effects are observed when either cultured neurons or glia cells are treated with pathophysiological concentrations of ammonia (Sánchez-Pérez and Felipo 2006;Rama Rao et al 2003;Chan et al 2003). For further readings on the effects of ammonia toxicity refer to reviews by Felipo and Butterworth (2002) and Cooper and Lai (1987).…”

Section: Consequential Effects Of Ammonia Toxicitymentioning

confidence: 80%

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: Consequential Effects Of Ammonia Toxicitymentioning

confidence: 80%

Identifying the direct effects of ammonia on the brain

2008

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“…Moreover, gene variants in EAAT2 influence reward dependence [82]. Dysfunction of EAAT3 may result in dicarboxylic aminoaciduria, which can be associated with mental retardation [83] and has been implicated in obsessive-compulsive disorder [83], schizophrenia [72,84,85], epilepsy [78] and hepatic encephalopathy [86]. EAAT4 has been associated with schizophrenia [72,84].…”

Section: Discussionmentioning

confidence: 99%

Regulation of the Glutamate Transporters by JAK2

Hosseinzadeh

Bhavsar²,

Sopjani³

et al. 2011

Cell Physiol Biochem

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The Janus-activated kinase-2 JAK2 is involved in the signaling of leptin and erythropoietin receptors and mediates neuroprotective effects of the hormones. In theory, JAK2 could be effective through modulation of the glutamate transporters, carriers accounting for the clearance of glutamate released during neurotransmission. The present study thus elucidated the effect of JAK2 on the glutamate transporters EAAT1, EAAT2, EAAT3 and EAAT4. To this end, cRNA encoding the carriers was injected into Xenopus oocytes with or without cRNA encoding JAK2 and glutamate transport was estimated from glutamate induced current (I_glu). I_glu was observed in Xenopus oocytes expressing EAAT1 or EAAT2 or EAAT3 or EAAT4, but not in water injected oocytes. Coexpression of JAK2 resulted in an increase of I_glu by 83% (EAAT1), 67% (EAAT2), 42% (EAAT3) and 126% (EAAT4). As shown for EAAT4 expressing Xenopus oocytes, the effect of JAK2 was mimicked by gain of function mutation ^V617FJAK2 but not by the inactive mutant ^K882EJAK2. Incubation with JAK2 inhibitor AG490 (40 µM) resulted in a gradual decrease of I_glu by 53%, 79% and 92% within 3, 6 and 24 hours. Confocal microscopy and chemiluminescence analysis revealed that JAK2 coexpression increased EAAT4 protein abundance in the cell membrane. Disruption of transcription did not appreciably modify the up-regulation of I_glu in EAAT4 expressing oocytes. The decay of I_glu following inhibition of carrier insertion with brefeldin A was similar in oocytes expressing EAAT4 + JAK2 and oocytes expressing EAAT4 alone, indicating that JAK2 did not appreciably affect carrier retrieval from the membrane. In conclusion, JAK2 is a novel powerful regulator of glutamate transporters and thus participates in the protection against excitotoxicity.

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“…Dysregulated activity of the SPAK/OSR1 pathway may lead to arterial hypertension and several diseases associated with neuronal hyperactivity, such as epilepsy, spasticity, neuropathic pain, schizophrenia, and autism [26]. Notably, lack of EAAT3 could similarly enhance neuronal excitability resulting in epilepsy [56,57,58,59,60], schizophrenia [61,62,63,64,65,66,67] and hepatic encephalopathy [68]. …”

Section: Discussionmentioning

confidence: 99%

SPAK and OSR1 Sensitivity of Excitatory Amino Acid Transporter EAAT3

Borrás

Salker²,

Elvira³

et al. 2015

Nephron

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Background/Aims: Kinases involved in the regulation of epithelial transport include SPAK (SPS1-related proline/alanine-rich kinase) and OSR1 (oxidative stress-responsive kinase 1). SPAK and OSR1 are both regulated by WNK (with-no-K(Lys)) kinases. The present study explored whether SPAK and/or OSR1 influence the excitatory amino acid transporter EAAT3, which accomplishes glutamate and aspartate transport in kidney, intestine and brain. Methods: cRNA encoding EAAT3 was injected into Xenopus laevis oocytes with or without additional injection of cRNA encoding wild-type SPAK, constitutively active ^T233ESPAK, WNK insensitive ^T233ASPAK, catalytically inactive ^D212ASPAK, wild-type OSR1, constitutively active ^T185EOSR1, WNK insensitive ^T185AOSR1 and catalytically inactive ^D164AOSR1. Glutamate-induced current was taken as measure of electrogenic glutamate transport and was quantified utilizing dual electrode voltage clamp. Furthermore, Ussing chamber was employed to determine glutamate transport in the intestine from gene-targeted mice carrying WNK insensitive SPAK (spak^tg/tg) and from corresponding wild-type mice (spak^+/+). Results: EAAT3 activity was significantly decreased by wild-type SPAK and ^T233ESPAK, but not by ^T233ASPAK and ^D212ASPAK. SPAK decreased maximal transport rate without affecting significantly affinity of the carrier. Similarly, EAAT3 activity was significantly downregulated by wild-type OSR1 and ^T185EOSR1, but not by ^T185AOSR1 and ^D164AOSR1. Again OSR1 decreased maximal transport rate without affecting significantly affinity of the carrier. Intestinal electrogenic glutamate transport was significantly lower in spak^+/+ than in spak^tg/tg mice. Conclusion: Both, SPAK and OSR1 are negative regulators of EAAT3 activity.

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Effects of ammonia on high affinity glutamate uptake and glutamate transporter EAAT3 expression in cultured rat cerebellar granule cells

Cited by 25 publications

References 42 publications

Identifying the direct effects of ammonia on the brain

Identifying the direct effects of ammonia on the brain

Regulation of the Glutamate Transporters by JAK2

SPAK and OSR1 Sensitivity of Excitatory Amino Acid Transporter EAAT3

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