The system N transporter SN2 doubles as a transmitter precursor furnisher and a potential regulator of NMDA receptors

Hamdani, El Hassan; Gudbrandsen, Marius; Bjørkmo, Mona; Chaudhry, Farrukh A.

doi:10.1002/glia.22386

Cited by 36 publications

(53 citation statements)

References 74 publications

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“…Indeed, a pharmacologic disruption of SAT2 abolishes retrograde signaling (33). Finally, the system N transporter SN2 is exclusively expressed on astroglial cell membranes and mediates electroneutral and bidirectional transport of several neutral amino acids (34, 35). SN2 participates in astroglial release of glutamine for neurotransmitter generation but adds on by releasing glycine for co-activation of NMDA receptors (35).…”

Section: The System N and System A Transporters Sustain Astroglial-tomentioning

confidence: 99%

Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Nissen‐Meyer¹,

Chaudhry²

2013

Front. Endocrinol.

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The system N transporter SN1 (also known as SNAT3) is enriched on perisynaptic astroglial cell membranes. SN1 mediates electroneutral and bidirectional glutamine transport, and regulates the intracellular as well as the extracellular concentrations of glutamine. We hypothesize that SN1 participates in the glutamate/γ-aminobutyric acid (GABA)-glutamine cycle and regulates the amount of glutamine supplied to the neurons for replenishment of the neurotransmitter pools of glutamate and GABA. We also hypothesize that its activity on the plasma membrane is regulated by protein kinase C (PKC)-mediated phosphorylation and that SN1 activity has an impact on synaptic plasticity. This review discusses reports on the regulation of SN1 by PKC and presents a consolidated model for regulation and degradation of SN1 and the subsequent functional implications. As SN1 function is likely also regulated by PKC-mediated phosphorylation in peripheral organs, the same mechanisms may, thus, have impact on e.g., pH regulation in the kidney, urea formation in the liver, and insulin secretion in the pancreas.

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Section: The System N and System A Transporters Sustain Astroglial-tomentioning

confidence: 99%

Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Nissen‐Meyer¹,

Chaudhry²

2013

Front. Endocrinol.

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“…Glutamine can be released to the extracellular fluid by a sodium neutral amino transporter in the astrocytic membrane by SNAT3 (Boulland et al 2002, 2003; Mackenzie and Erickson 2004; Nissen-Meyer et al 2011) and SNAT5 (SN2; slc38a5) (Hamdani et al 2012) because it is inactive in the sense that it cannot activate glutamate receptors (for review: Erecinska and Silver 1990; Danbolt 2001; Hertz 2013). The conversion of glutamate to glutamine is catalyzed by the enzyme glutamine synthetase (GLUL) in an ATP-dependent manner (Erecinska and Silver 1990; Marcaggi and Coles 2001).…”

Section: Comments On the Glutamine-glutamate Cyclementioning

confidence: 99%

Glutamate as a neurotransmitter in the healthy brain

2014

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Glutamate is the most abundant free amino acid in the brain and is at the crossroad between multiple metabolic pathways. Considering this, it was a surprise to discover that glutamate has excitatory effects on nerve cells, and that it can excite cells to their death in a process now referred to as “excitotoxicity”. This effect is due to glutamate receptors present on the surface of brain cells. Powerful uptake systems (glutamate transporters) prevent excessive activation of these receptors by continuously removing glutamate from the extracellular fluid in the brain. Further, the blood–brain barrier shields the brain from glutamate in the blood. The highest concentrations of glutamate are found in synaptic vesicles in nerve terminals from where it can be released by exocytosis. In fact, glutamate is the major excitatory neurotransmitter in the mammalian central nervous system. It took, however, a long time to realize that. The present review provides a brief historical description, gives a short overview of glutamate as a transmitter in the healthy brain, and comments on the so-called glutamate–glutamine cycle. The glutamate transporters responsible for the glutamate removal are described in some detail.

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“…This may be by means of neutral amino acid transporters in the astrocytic membrane (Mackenzie and Erickson, 2004;Nissen-Meyer et al, 2011;Hamdani et al, 2012;Bhutia and Ganapathy, 2015), but there are several possible mechanisms including channels (for review see: Malarkey and Parpura, 2008).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Neuronal vs glial glutamate uptake: Resolving the conundrum

Danbolt

Furness

Zhou

2016

Neurochemistry International

177

152

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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.

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The system N transporter SN2 doubles as a transmitter precursor furnisher and a potential regulator of NMDA receptors

Cited by 36 publications

References 74 publications

Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Protein Kinase C Phosphorylates the System N Glutamine Transporter SN1 (Slc38a3) and Regulates Its Membrane Trafficking and Degradation

Glutamate as a neurotransmitter in the healthy brain

Neuronal vs glial glutamate uptake: Resolving the conundrum

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