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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) Predicted secondary structure of the human vesicular monoamine transporter 2 (VMAT2) and (B) two classical and now commonly used VMAT inhibitors: tetrabenazine and reserpine (Wimalasena, 2010). (C) Three dimensional homology model of the vesicular acetylcholine transporter (VAChT) (Khare et al., 2010) and (D) its most studied inhibitor: vesamicol (Kozaka et al., 2012).
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Figure 4: (A) Predicted secondary structure of the human vesicular monoamine transporter 2 (VMAT2) and (B) two classical and now commonly used VMAT inhibitors: tetrabenazine and reserpine (Wimalasena, 2010). (C) Three dimensional homology model of the vesicular acetylcholine transporter (VAChT) (Khare et al., 2010) and (D) its most studied inhibitor: vesamicol (Kozaka et al., 2012).

Mentions: Sequence analysis of human VMAT2 unveilled that most variable regions are located near the N- and C-terminal and in the large glycosylated loop between TMD I and II (Figure 4A) (Wimalasena, 2010). Biochemical studies (Thiriot and Ruoho, 2001; Thiriot et al., 2002) demonstrated that Cys 430 in TMD XI is essential for the recognition and binding of VMAT inhibitors. Moreover, using a recombinant VMAT2 construct with a thrombin cleavage site between TMD VI and VII demonstrated that Cys 117 in the loop between TMD I and II and Cys 324 in the loop between TMD VII and VIII form a disulfide bond in human VMAT2, which contributes to the structural integrity and efficient monoamine transport (Wimalasena, 2010). The structure is predicted by usingTMbase-A database of membrane spanning protein segments. Distinct conserved amino acids in human VMAT1, human VMAT2, rat VMAT1, rat VMAT2, and bovine VMAT2 are colored. The shown amino acid numbering is based on the sequence of human VMAT2 (Wimalasena, 2010).


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) Predicted secondary structure of the human vesicular monoamine transporter 2 (VMAT2) and (B) two classical and now commonly used VMAT inhibitors: tetrabenazine and reserpine (Wimalasena, 2010). (C) Three dimensional homology model of the vesicular acetylcholine transporter (VAChT) (Khare et al., 2010) and (D) its most studied inhibitor: vesamicol (Kozaka et al., 2012).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 4: (A) Predicted secondary structure of the human vesicular monoamine transporter 2 (VMAT2) and (B) two classical and now commonly used VMAT inhibitors: tetrabenazine and reserpine (Wimalasena, 2010). (C) Three dimensional homology model of the vesicular acetylcholine transporter (VAChT) (Khare et al., 2010) and (D) its most studied inhibitor: vesamicol (Kozaka et al., 2012).
Mentions: Sequence analysis of human VMAT2 unveilled that most variable regions are located near the N- and C-terminal and in the large glycosylated loop between TMD I and II (Figure 4A) (Wimalasena, 2010). Biochemical studies (Thiriot and Ruoho, 2001; Thiriot et al., 2002) demonstrated that Cys 430 in TMD XI is essential for the recognition and binding of VMAT inhibitors. Moreover, using a recombinant VMAT2 construct with a thrombin cleavage site between TMD VI and VII demonstrated that Cys 117 in the loop between TMD I and II and Cys 324 in the loop between TMD VII and VIII form a disulfide bond in human VMAT2, which contributes to the structural integrity and efficient monoamine transport (Wimalasena, 2010). The structure is predicted by usingTMbase-A database of membrane spanning protein segments. Distinct conserved amino acids in human VMAT1, human VMAT2, rat VMAT1, rat VMAT2, and bovine VMAT2 are colored. The shown amino acid numbering is based on the sequence of human VMAT2 (Wimalasena, 2010).

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