Glutamine Is Required for Persistent Epileptiform Activity in the Disinhibited Neocortical Brain Slice

Tani, Hiroshi; Dulla, Chris G.; Huguenard, John R.; Reimer, Richard J.

doi:10.1523/jneurosci.0106-09.2010

Cited by 55 publications

(57 citation statements)

References 69 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…2). Owing to the importance of the glutamateglutamine cycle for replenishment of neurotransmitter pools (69,(93)(94)(95), inhibition of glycogen degradation may lead to decrements in neuronal glutamate synthesis. In agreement with this, it was demonstrated that glutamate-glutamine cycle activity (Fig.…”

Section: Role Of Glycogen Phosphorylase Isoforms For Glycogen Shunt Amentioning

confidence: 99%

Astrocytic glycogen metabolism in the healthy and diseased brain

Bak¹,

Walls²,

Schousboe

et al. 2018

Journal of Biological Chemistry

120

View full text Add to dashboard Cite

Section: Role Of Glycogen Phosphorylase Isoforms For Glycogen Shunt Amentioning

confidence: 99%

Astrocytic glycogen metabolism in the healthy and diseased brain

Bak¹,

Walls²,

Schousboe

et al. 2018

Journal of Biological Chemistry

120

View full text Add to dashboard Cite

“…The prevailing view, however, has been that glutamine released from astrocytes is the predominant source of glutamate in glutamatergic terminals (Van den Berg and M A N U S C R I P T Garfinkel, 1971;Benjamin and Quastel, 1972;Hertz et al, 1999;Sibson et al, 2001) especially in situations of high demand such as persistent epileptiform activity (Tani et al, 2010;Tani et al, 2014). The idea has been that glutamate is taken up by astrocytes, converted to glutamine by the action of the astroglial enzyme glutamine synthetase (GS) in an ATP-dependent manner, released, taken up by axon-terminals and converted back to glutamate by means of phosphate activated glutaminase (Erecinska and Silver, 1990;Marcaggi and Coles, 2001;Hertz, 2013).…”

Section: Eaat2 In Terminals Will Short-circuit the Glutamate-glutaminmentioning

confidence: 99%

Neuronal vs glial glutamate uptake: Resolving the conundrum

Danbolt

Furness

Zhou

2016

Neurochemistry International

186

152

View full text Add to dashboard Cite

Neither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that both astrocytes and neurons express glutamate transporters. However, the relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) a hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox. ABBREVIATIONSCre, Cyclization recombinase (Le and Sauer, 2000); EAAC1, glutamate transporter (EAAT3; slc1a1; Kanai and Hediger, 1992; Bjørås et al., 1996); EAAT, excitatory amino acid transporter (synonym to glutamate transporter); GABA, γ-aminobutyric acid; GLAST, rat glutamate transporter (EAAT1; slc1a3; Storck et al., 1992;Tanaka, 1993a); GLT-1, rat glutamate transporter (EAAT2; slc1a2; Pines et al., 1992); GLUL, glutamine synthetase; TBOA, DL-threo-β-benzyloxyaspartate AbstractNeither normal brain function nor the pathological processes involved in neurological diseases can be adequately understood without knowledge of the release, uptake and metabolism of glutamate. The reason for this is that glutamate (a) is the most abundant amino acid in the brain, (b) is at the cross-roads between several metabolic pathways, and (c) serves as the major excitatory neurotransmitter. In fact most brain cells express glutamate receptors and are thereby influenced by extracellular glutamate. In agreement, brain cells have powerful uptake systems that constantly remove glutamate from the extracellular fluid and thereby limit receptor activation. It has been clear since the 1970s that astrocytes and neurons express glutamate transporters. The relative contribution of neuronal and glial transporters to the total glutamate uptake activity, however, as well as their functional importance, has been hotly debated ever since. The present short review provides (a) an overview of what we know about neuronal glutamate uptake as well as an historical description of how we got there, and (b) an hypothesis reconciling apparently contradicting observations thereby possibly resolving the paradox.

show abstract

“…Indeed, glial cells are enriched with G-protein-coupled receptors, and their activation by glutamate, GABA, or other neurotransmitters are important endogenous triggers of PKC activation (Beckman et al, 1999). Complementary expression of both system A and non-system A transporters has been demonstrated on neurons, and it has been shown that the availability of glutamine regulates generation of the fast neurotransmitters (Rae et al, 2003;Jenstad et al, 2009;Solbu et al, 2010;Tani et al, 2010) and shapes the quantal size Liang et al, 2006;Fricke et al, 2007). Thus, SN1 may represent a key target for regulation of the glutamate/GABA-glutamine cycle (Fig.…”

Section: Functional Implications Of Sn1 Phosphorylationmentioning

confidence: 99%

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Nissen‐Meyer¹,

Popescu²,

Hamdani³

et al. 2011

J. Neurosci.

View full text Add to dashboard Cite

Molecular mechanisms involved in the replenishment of the fast neurotransmitters glutamate and GABA are poorly understood. Glutamine sustains their generation. However, glutamine formation from the recycled transmitters is confined to glial processes and requires facilitators for its translocation across the glial and neuronal membranes. Indeed, glial processes are enriched with the system N transporter SN1 (Slc38a3), which, by bidirectional transport, maintains steady extracellular glutamine levels and thereby furnishes neurons with the primary precursor for fast neurotransmitters. We now demonstrate that SN1 is phosphorylated by protein kinase C␣ (PKC␣) and PKC␥. Electrophysiological characterization shows that phosphorylation reduces V max dramatically, whereas no significant effects are seen on the K m . Phosphorylation occurs specifically at a single serine residue (S52) in the N-terminal rat (Rattus norvegicus) SN1 and results in sequestration of the protein into intracellular reservoirs. Prolonged activation of PKC results in partial degradation of SN1. These results provide the first demonstration of phosphorylation of SN1 and regulation of its activity at the plasma membrane. Interestingly, membrane trafficking of SN1 resembles that of the glutamate transporter GLT and the glutamate-aspartate transporter GLAST: it involves the same PKC isoforms and occurs in the same glial processes. This suggests that the glutamate/GABA-glutamine cycle may be modified at two key points by similar signaling events and unmasks a prominent role for PKC-dependent phosphorylation. Our data suggest that extracellular glutamine levels may be fine-tuned by dynamic regulation of glial SN1 activity, which may impact on transmitter generation, contribute to defining quantal size, and have profound effects on synaptic plasticity.

show abstract

Glutamine Is Required for Persistent Epileptiform Activity in the Disinhibited Neocortical Brain Slice

Cited by 55 publications

References 69 publications

Astrocytic glycogen metabolism in the healthy and diseased brain

Astrocytic glycogen metabolism in the healthy and diseased brain

Neuronal vs glial glutamate uptake: Resolving the conundrum

Protein Kinase C-Mediated Phosphorylation of a Single Serine Residue on the Rat Glial Glutamine Transporter SN1 Governs Its Membrane Trafficking

Contact Info

Product

Resources

About