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Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

Van Liefferinge J, Massie A, Portelli J, Di Giovanni G, Smolders I - Front Cell Neurosci (2013)

Bottom Line: We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain.We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery.Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurosciences, Vrije Universiteit Brussel Brussels, Belgium.

ABSTRACT
The vesicular neurotransmitter transporters (VNTs) are small proteins responsible for packing synaptic vesicles with neurotransmitters thereby determining the amount of neurotransmitter released per vesicle through fusion in both neurons and glial cells. Each transporter subtype was classically seen as a specific neuronal marker of the respective nerve cells containing that particular neurotransmitter or structurally related neurotransmitters. More recently, however, it has become apparent that common neurotransmitters can also act as co-transmitters, adding complexity to neurotransmitter release and suggesting intriguing roles for VNTs therein. We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain. We will focus on evidence regarding transgenic mice with disruptions in VNTs in different models of seizures and epilepsy. We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery. Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.

No MeSH data available.


Related in: MedlinePlus

A two and three dimensional molecular structure of the members of the SLC17 family. (A,B) The vesicular glutamate transporter 1 (VGLUT1) (Almqvist et al., 2007), (D,E) the vesicular excitatory amino acid transporter (VEAT) (Courville et al., 2010) and (G) the vesicular nucleotide transporter (VNUT) (Sawada et al., 2008). (C) The different families of VGLUT modulators (Pietrancosta et al., 2010). (F) The most bioactive analog of sialic acid: per-O-Ac,9-iodo-Neu5Ac and the novel VEAT ligand identified by virtual high-throughput screening: FR139317 (Pietrancosta et al., 2012). (H) 4,4′-diisothiocyanatostilbene-2,2′-disulfonate, the only known inhibitor of ATP transport in vitro.
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Figure 3: A two and three dimensional molecular structure of the members of the SLC17 family. (A,B) The vesicular glutamate transporter 1 (VGLUT1) (Almqvist et al., 2007), (D,E) the vesicular excitatory amino acid transporter (VEAT) (Courville et al., 2010) and (G) the vesicular nucleotide transporter (VNUT) (Sawada et al., 2008). (C) The different families of VGLUT modulators (Pietrancosta et al., 2010). (F) The most bioactive analog of sialic acid: per-O-Ac,9-iodo-Neu5Ac and the novel VEAT ligand identified by virtual high-throughput screening: FR139317 (Pietrancosta et al., 2012). (H) 4,4′-diisothiocyanatostilbene-2,2′-disulfonate, the only known inhibitor of ATP transport in vitro.

Mentions: In Figures 3A,B, the 2D and 3D molecular structure of VGLUT1 are shown, based on transmembrane segment prediction and topology of bacterial MFS proteins. Filled black circles represent residues facing the center of the pore (gray volume) that is open to the cytoplasmic side. Three arginine residues (R80 from helix 1, R176 from helix 4, and R314 from helix 7) that are exposed to the pore are shown in sticks. The first and last highly variable 60 residues of the N- and C-terminal are not shown in the 3D model (Almqvist et al., 2007).


Are vesicular neurotransmitter transporters potential treatment targets for temporal lobe epilepsy?

Van Liefferinge J, Massie A, Portelli J, Di Giovanni G, Smolders I - Front Cell Neurosci (2013)

A two and three dimensional molecular structure of the members of the SLC17 family. (A,B) The vesicular glutamate transporter 1 (VGLUT1) (Almqvist et al., 2007), (D,E) the vesicular excitatory amino acid transporter (VEAT) (Courville et al., 2010) and (G) the vesicular nucleotide transporter (VNUT) (Sawada et al., 2008). (C) The different families of VGLUT modulators (Pietrancosta et al., 2010). (F) The most bioactive analog of sialic acid: per-O-Ac,9-iodo-Neu5Ac and the novel VEAT ligand identified by virtual high-throughput screening: FR139317 (Pietrancosta et al., 2012). (H) 4,4′-diisothiocyanatostilbene-2,2′-disulfonate, the only known inhibitor of ATP transport in vitro.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3757300&req=5

Figure 3: A two and three dimensional molecular structure of the members of the SLC17 family. (A,B) The vesicular glutamate transporter 1 (VGLUT1) (Almqvist et al., 2007), (D,E) the vesicular excitatory amino acid transporter (VEAT) (Courville et al., 2010) and (G) the vesicular nucleotide transporter (VNUT) (Sawada et al., 2008). (C) The different families of VGLUT modulators (Pietrancosta et al., 2010). (F) The most bioactive analog of sialic acid: per-O-Ac,9-iodo-Neu5Ac and the novel VEAT ligand identified by virtual high-throughput screening: FR139317 (Pietrancosta et al., 2012). (H) 4,4′-diisothiocyanatostilbene-2,2′-disulfonate, the only known inhibitor of ATP transport in vitro.
Mentions: In Figures 3A,B, the 2D and 3D molecular structure of VGLUT1 are shown, based on transmembrane segment prediction and topology of bacterial MFS proteins. Filled black circles represent residues facing the center of the pore (gray volume) that is open to the cytoplasmic side. Three arginine residues (R80 from helix 1, R176 from helix 4, and R314 from helix 7) that are exposed to the pore are shown in sticks. The first and last highly variable 60 residues of the N- and C-terminal are not shown in the 3D model (Almqvist et al., 2007).

Bottom Line: We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain.We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery.Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.

View Article: PubMed Central - PubMed

Affiliation: Center for Neurosciences, Vrije Universiteit Brussel Brussels, Belgium.

ABSTRACT
The vesicular neurotransmitter transporters (VNTs) are small proteins responsible for packing synaptic vesicles with neurotransmitters thereby determining the amount of neurotransmitter released per vesicle through fusion in both neurons and glial cells. Each transporter subtype was classically seen as a specific neuronal marker of the respective nerve cells containing that particular neurotransmitter or structurally related neurotransmitters. More recently, however, it has become apparent that common neurotransmitters can also act as co-transmitters, adding complexity to neurotransmitter release and suggesting intriguing roles for VNTs therein. We will first describe the current knowledge on vesicular glutamate transporters (VGLUT1/2/3), the vesicular excitatory amino acid transporter (VEAT), the vesicular nucleotide transporter (VNUT), vesicular monoamine transporters (VMAT1/2), the vesicular acetylcholine transporter (VAChT) and the vesicular γ-aminobutyric acid (GABA) transporter (VGAT) in the brain. We will focus on evidence regarding transgenic mice with disruptions in VNTs in different models of seizures and epilepsy. We will also describe the known alterations and reorganizations in the expression levels of these VNTs in rodent models for temporal lobe epilepsy (TLE) and in human tissue resected for epilepsy surgery. Finally, we will discuss perspectives on opportunities and challenges for VNTs as targets for possible future epilepsy therapies.

No MeSH data available.


Related in: MedlinePlus