Recent Molecular Advances in Mammalian Glutamine Transport

Bode, Barrie P.

doi:10.1093/jn/131.9.2475s

Cited by 219 publications

(187 citation statements)

References 96 publications

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“…Glu uptake appears to be modulated molecularly on virtually all possible levels including DNA transcription, mRNA splicing and degradation, protein synthesis and targeting, actual AA transport activity and associated ion channel activities. A number of soluble compounds, including Glu, cytokines, and growth factors, influence the GluTP expression and activities 121 .…”

Section: ) Glutamatementioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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Seventy years ago it was discovered that glutamate is abundant in the brain and that it plays a central role in brain metabolism. However, it took the scientific community a long time to realize that glutamate also acts as a neurotransmitter. Glutamate is an amino acid and brain tissue contains as much as 5 -15 mM glutamate per kg depending on the region, which is more than of any other amino acid. The main motivation for the ongoing research on glutamate is due to the role of glutamate in the signal transduction in the nervous systems of apparently all complex living organisms, including man. Glutamate is considered to be the major mediator of excitatory signals in the mammalian central nervous system and is involved in most aspects of normal brain function including cognition, memory and learning. In this review, the basic biology of the excitatory amino acids glutamate, glutamate receptors, GABA, and glycine will first be explored. In the second part of this review, the known pathophysiology and pathology will be described. (J Toxicol Pathol 2008; 21: 25-51)

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Section: ) Glutamatementioning

confidence: 99%

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Rousseaux

2008

J Toxicol Pathol

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“…HCl, saturated aq. NaHCO 3 and brine, dried and evaporated to give 1 as white crystals (1.57 g, 70 %), mp 156-158 °C (EtOAc-hexanes); 1 …”

Section: Synthesis Of Mni-alanine: 1-[2s-2-(tert-butoxycarbonylamino)mentioning

confidence: 99%

“…NaHCO 3 and brine, dried and evaporated. Flash chromatography [EtOAc-hexanes (1:4)] followed by trituration with Et 2 O-hexanes gave 2 as white crystals (1.04 g, 82 %), mp 56-58 °C (hexanes); 1 …”

Section: -[2s-2-(di-tert-butoxycarbonylamino)propanoyl]-4-methoxyindmentioning

confidence: 99%

Pre-steady-State Currents in Neutral Amino Acid Transporters Induced by Photolysis of a New Caged Alanine Derivative

et al. 2007

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Na + -dependent transmembrane transport of the small neutral amino acids, such as glutamine and alanine, is mediated, among others, by the neutral amino acid transporters of the solute carrier 1 (SLC1, ASCT1 and 2) and SLC38 families (SNAT1, 2 and 4). Many mechanistic aspects of amino acid transport by these systems are not well understood. Here, we describe a new photolabile alanine derivative, based on protection of alanine with the 4-methoxy-7-nitroindolinyl (MNI) caging group, which we use for pre-steady-state kinetic analysis of alanine transport by ASCT2 and SNAT1 and 2. MNI-alanine has favorable photochemical properties and is stable in aqueous solution. It is also inert with respect to the transport systems studied. Photolytic release of free alanine results in the generation of significant transient current components in HEK293 cells expressing the ASCT2, SNAT1 and SNAT2 proteins. In ASCT2, these currents show biphasic decay with time constants, τ, in the 1-30 ms time range. They are fully inhibited in the absence of extracellular Na + , demonstrating that Na + binding to the transporter is necessary for induction of the alanine-mediated current. For SNAT1, these transient currents differ in their time course (τ = 1.6 ms) from previously described pre-steady-state currents generated by applying steps in the membrane potential (τ ~ 4-5 ms), indicating that they are associated with a fast, previously undetected, electrogenic partial reaction in the SNAT1 transport cycle. The implications of these results for the mechanisms of transmembrane transport of alanine are discussed. The new caged alanine derivative will provide a useful tool for future, more detailed studies of neutral amino acid transport.Neutral amino acids are transported across cell membranes by a variety of transport systems [reviewed in (1)]. Some of these systems, which actively transport neutral amino acids against a concentration gradient, are powered by cotransport of Na + down its own transmembrane concentration gradient. For small neutral amino acids these systems include System N, System A, and System ASC. System N and System A belong to the same solute carrier (SLC) protein family (SLC38) and the known cloned members of this family have collectively been termed sodium-coupled neutral amino acid transporters (SNAT) (2). Members 1, 2 and 4 of this family are thought to belong to the System A class (3,4), whereas members 3 and 5 belong to the System N class (5,6). In contrast, System ASC transporters belong to the SLC1 family of transport proteins and the cloned members ASCT1 and ASCT2 have a high degree of sequence similarity with glutamate transporters (7-9). † This work was supported by a grant by the Florida Department of Health (04NIR-07) awarded to CG. Pre-steady-state kinetic techniques have been used in the past to study details of the transport mechanism of ion pumps (10,11) and secondary transporters (12)(13)(14). One means to obtain pre-steady-state kinetic data is to disturb an existing transporter steady state by a...

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“…In this model, released glutamate is taken up by astrocytes and converted to glutamine [34,35]. Glutamine is exported from the glia via the neutral amino acid transport system N. Then, the neutral amino acid transport system A transports glutamine into the neuron [28][29][30], where it is converted back to glutamate [36].…”

Section: Unc-47: What Protein Is the Vesicular Gaba Transporter?mentioning

confidence: 99%

The GABA nervous system in C. elegans

Schuske

Beg

Jørgensen

2004

Trends in Neurosciences

163

151

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GABA neurotransmission requires a specialized set of proteins to synthesize, transport or respond to GABA. This article reviews results from a genetic strategy in the nematode Caenorhabditis elegans designed to identify the genes responsible for these activities. These studies identified mutations in genes encoding five different proteins: the biosynthetic enzyme for GABA, the vesicular GABA transporter, a transcription factor that determines GABA neuron identity, a classic inhibitory GABA receptor and a novel excitatory GABA receptor. This review discusses the strategy employed to identify these genes as well as the conclusions about GABA transmission derived from study of the mutant phenotypes.Activity in the vertebrate brain depends on a yin and yang balance between excitatory and inhibitory neurotransmission. A deficit of excitatory neurotransmission will lead to unconsciousness; a deficit of inhibitory neurotransmission will lead to epileptic seizures. The most abundant inhibitory neurotransmitter in the brain is GABA. Normal GABA function requires specialized proteins such as biosynthetic enzymes, transporters and receptors. Defects in these proteins can lead to a specific imbalance of GABA neurotransmission and lead to diseases. For example, mutations in the a1 and g2 GABA receptor subunits can cause familial forms of epilepsy [1 -3].Over ten years ago, a strategy was devised to identify the proteins specialized for GABA function using a genetic approach in the nematode Caenorhabditis elegans [4,5]. These studies have lead to some important discoveries. Specifically, the vesicular GABA transporter (VGAT) was first discovered in C. elegans and this sequence was used to identify the mammalian homolog [6]. The homeodomain protein UNC-30 identified a class of transcription factors required for multiple aspects of GABA neuron identity [7,8]. These studies also revealed the first cation-selective GABA receptor [9]. This review will discuss first the strategy used to identify proteins required for GABA neurotransmission in C. elegans and then the impact that their discovery has had on our understanding of GABA function. StrategyTo define the proteins required for GABA function, McIntire and colleagues looked for mutations in the nematode C. elegans that specifically disrupted GABAmediated behaviors [4,5]. To identify the GABA-containing cells in C. elegans, animals were stained using antibodies against the neurotransmitter. Antibody staining revealed that 26 of the 302 neurons present in C. elegans express the neurotransmitter GABA (Figure 1a). These 26 GABApositive neurons comprise six DD neurons, 13 VD neurons, four RME neurons, an RIS neuron, an AVL neuron and a DVB neuron (Figure 1b). These neurons fall into different classes based on their synaptic outputs: the D-type neurons -that is, the DD and VD motor neuronsinnervate the dorsal and ventral body muscles, respectively; the RME motor neurons innervate the head muscles; the AVL and DVB motor neurons innervate the enteric muscles; and RIS is an interneuron ...

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Recent Molecular Advances in Mammalian Glutamine Transport

Cited by 219 publications

References 96 publications

A Review of Glutamate Receptors I: Current Understanding of Their Biology

A Review of Glutamate Receptors I: Current Understanding of Their Biology

Pre-steady-State Currents in Neutral Amino Acid Transporters Induced by Photolysis of a New Caged Alanine Derivative

The GABA nervous system in C. elegans

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