Glycine Transporter 1 Inhibitors and Modulation of NMDA Receptor-Mediated Excitatory Neurotransmission

Sur, Cyrille; Kinney, Gene G.

doi:10.2174/138945007780618535

Cited by 54 publications

(28 citation statements)

References 51 publications

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“…Alternatively, B 0 AT3 might function to remove a neurochemically active substrate from the synapse. For example, proline and glycine, both likely substrates for B 0 AT3, have been shown to modulate glutamatergic signaling (30,31). It is interesting to note that PROT, B 0 AT2, B 0 AT3, and the brain-specific isoform of the imino transporter are all expressed with relative specificity in the brain and all transport proline with apparent affinities in the submillimolar range.…”

Section: Discussionmentioning

confidence: 99%

Synaptic Vesicle Protein NTT4/XT1 (SLC6A17) Catalyzes Na+-coupled Neutral Amino Acid Transport

Zaia

Reimer

2009

Journal of Biological Chemistry

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The SLC6 family of structurally related, Na ؉ -dependent transporter proteins is responsible for presynaptic reuptake of the majority of neurotransmitters. Within this family are a number of orphan transporters, including NTT4/XT1 (SLC6A17), a protein first identified over 15 years ago. NTT4/XT1 is expressed exclusively in the nervous system and specifically on synaptic vesicles in glutamatergic and some GABAergic neurons. Despite extensive efforts by a number of groups, no substrate has been reported for NTT4/XT1. Here we use a combination of molecular manipulations to increase expression of the NTT4/XT1 protein at the plasma membrane and to directly demonstrate that it catalyzes neutral amino acid transport. The substrate profile of the NTT4/XT1-dependent activity is similar to that of the closely related B 0 AT2/SBAT1 (SLC6A15), including a submillimolar apparent affinity for proline and leucine and a low millimolar apparent affinity for glutamine. The transport activity is Na ؉ -dependent and Cl ؊ -independent and is inhibited by low pH as is SLC6A15, suggesting redundant roles for these proteins. This characterization of NTT4/XT1 offers important insights into neurotransmitter metabolism as well as the mechanistic differences among the structurally related, but functionally divergent, SLC6 proteins.Synaptic transmission places a great metabolic burden upon neurons. The thousands of neurotransmitter molecules released with fusion of each synaptic vesicle must be replenished. The most direct mechanism of compensating for exocytotic release is presynaptic reuptake of the neurotransmitter through plasma membrane transporters. Such a reuptake mechanism is used by several types of neurons, including those that release GABA, 2 glycine, and monoamines. The fates of synaptically released acetylcholine and glutamate are more complex; acetylcholine is hydrolyzed to acetate and choline in the synaptic cleft, and synaptically released glutamate is readily taken up by astrocytes, precluding direct neuronal reuptake of these neurotransmitters. Although acetylcholine is hydrolyzed in the synaptic cleft, a presynaptic transport system for the choline portion of the neurotransmitter is expressed in cholinergic neurons (1). Glutamate cleared from the synapse by astrocytes is rapidly converted to glutamine and shuttled back into neurons for reconversion to glutamate (2). Despite the efficiency of astrocytic glutamate uptake, it is estimated that at least 25% of the synaptically released glutamate exits this glutamate-glutamine cycle (3), suggesting that glutamatergic neurons must rely on additional transport mechanisms for uptake of neurotransmitter precursors.The SLC6 family, a group of structurally related, Na ϩ -dependent transporter proteins, is responsible for presynaptic reuptake of the majority of neurotransmitters (4, 5). These transporters can be subdivided into the following groups on the basis of structure: 1) a monoamine transporter group (DAT, NET, and SERT); 2) a GABA transporter group that includes GAT1-3 as wel...

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Section: Discussionmentioning

confidence: 99%

Synaptic Vesicle Protein NTT4/XT1 (SLC6A17) Catalyzes Na+-coupled Neutral Amino Acid Transport

Zaia

Reimer

2009

Journal of Biological Chemistry

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“…These experiments suggested that this down-regulation might be associated with the trafficking of the transporter, although the molecular mechanisms behind this process remained unexplored. Because GLYT1 is a major regulator of the concentration of glycine both at inhibitory and excitatory synapses, it represents a target for potentially important drugs with antipsychotic and analgesic properties (6). Thus, we have further investigated the mechanisms involved in the endocytic trafficking of this transporter.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, mice lacking GLYT1 have impaired glycinergic neurotransmission, which has been attributed to an increase in extracellular glycine close to the strychnine-sensitive glycine receptor (4). Moreover, GLYT1 has been identified in neuronal elements closely associated with the glutamatergic pathways throughout the brain (5,6). GLYT1 is enriched in presynaptic buttons, where it largely co-localizes with the vesicular glutamate transporter vGLUT1.…”

mentioning

confidence: 99%

Constitutive and Regulated Endocytosis of the Glycine Transporter GLYT1b Is Controlled by Ubiquitination

Fernández-Sánchez¹,

Villarreal²,

Giménez³

et al. 2009

Journal of Biological Chemistry

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The glycine transporter GLYT1 regulates both glycinergic and glutamatergic neurotransmission by controlling the reuptake of glycine at synapses. Trafficking of GLYT1 to and from the cell surface is critical for its function. Activation of PKC down-regulates the activity of GLYT1 through a mechanism that has so far remained uncharacterized. Here we show that GLYT1b undergoes fast constitutive endocytosis that is accelerated by phorbol esters. Both constitutive and regulated endocytosis occur through a dynamin 2-and clathrin-dependent pathway, accumulating in the transporter in transferrin-containing endosomes. A chimera with the extracellular and transmembrane domains of the nerve growth factor receptor and the COOH-terminal tail of GLYT1 was efficiently internalized through this clathrin pathway, suggesting the presence of molecular determinants for GLYT1b endocytosis in its COOH-terminal tail. Extensive site-directed mutagenesis in this region of the chimera highlighted the involvement of lysine residues in its internalization. In the context of the full-length transporter, lysine 619 played a prominent role in both the constitutive and phorbol 12-myristate 13-acetate-induced endocytosis of GLYT1b, suggesting the involvement of ubiquitin modification of GLYT1b during the internalization process. Indeed, we show that GLYT1b undergoes ubiquitination and that this process is stimulated by phorbol 12-myristate 13-acetate. In addition, this endocytosis is impaired in an ubiquitination-deficient cell line, further evidence that constitutive and regulated endocytosis of GLYT1b is ubiquitin-dependent. It remains to be determined whether GLYT1b recycling might be affected in pathologies involving alterations to the ubiquitin system, thereby interfering with its influence on inhibitory and excitatory neurotransmission.Glycine fulfills a dual role in neurotransmission by mediating inhibition through the strychnine-sensitive glycine receptor and excitation as a co-agonist of the NMDA 2 receptors (1, 2). Although it was initially believed that the concentration of glycine in the synaptic cleft would be sufficient to saturate the glycine sites on NMDA receptors, recent pharmacological and electrophysiological evidence indicates that due to the activity of the GLYT1 (glycine transporter-1) glycine transporter, this is probably not the case. Three isoforms of GLYT1 exist that differ in their NH 2 -terminal sequence (GLYT1a, GLYT1b, and GLYT1c), and they are strongly expressed in glycinergic areas of the nervous system, predominantly in glial cells (3). Indeed, mice lacking GLYT1 have impaired glycinergic neurotransmission, which has been attributed to an increase in extracellular glycine close to the strychnine-sensitive glycine receptor (4). Moreover, GLYT1 has been identified in neuronal elements closely associated with the glutamatergic pathways throughout the brain (5, 6). GLYT1 is enriched in presynaptic buttons, where it largely co-localizes with the vesicular glutamate transporter vGLUT1. It is also present in the posts...

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“…The more advanced target is the inhibition of glycine reuptake by GlyT1 in the perisynaptic region (Javitt, 2008(Javitt, , 2009. Preclinical studies indicate GlyT1 inhibitors augment NMDA receptor-dependent processes in vitro and in vivo (Sur and Kinney, 2007;Bridges et al, 2008;Yang and Svensson, 2008). Clinical proof of concept has been obtained with sarcosine, a naturally occurring intermediate in glycine metabolism that is a low-affinity GlyT1 inhibitor (Zhang et al, 2009a,b).…”

Section: F N-methyl-d-aspartate Receptor Potentiationmentioning

confidence: 99%

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

et al. 2010

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Glycine Transporter 1 Inhibitors and Modulation of NMDA Receptor-Mediated Excitatory Neurotransmission

Cited by 54 publications

References 51 publications

Synaptic Vesicle Protein NTT4/XT1 (SLC6A17) Catalyzes Na+-coupled Neutral Amino Acid Transport

Synaptic Vesicle Protein NTT4/XT1 (SLC6A17) Catalyzes Na+-coupled Neutral Amino Acid Transport

Constitutive and Regulated Endocytosis of the Glycine Transporter GLYT1b Is Controlled by Ubiquitination

Glutamate Receptor Ion Channels: Structure, Regulation, and Function

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