Neurotransmitter transporters: molecular function of important drug targets

Gether, Ulrik; Andersen, Peter Bøgh; Larsson, Orla M.; Schousboe, Arne

doi:10.1016/j.tips.2006.05.003

Cited by 295 publications

(235 citation statements)

References 67 publications

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“…318 Vesicular transporters serve to transport specific neurotransmitters into synaptic vesicles, including glutamate (VGLUT1-3), GABA and glycine (VGAT/ VIAAT), acetylcholine (VAC), and biogenic amines (catecholamines and serotonin) (VMAT). Changes in the function or expression of these transporters can modify the quantal size of synaptic potentials.…”

Section: Neurotransmitter Transportersmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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Section: Neurotransmitter Transportersmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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“…hGAT-1 is essential for the termination of neurotransmission by removing GABA from the synaptic cleft. Other important members of the family of sodium and chloride dependent neurotransmitter transporters (SLC6) are specialised to transport other neurotransmitters like glycine, dopamine, norepinephrine, or serotonine [4][5][6]. The recent determination of the crystal structure of a prokaryotic Na + /Cl --dependent leucine transporter from Aquifex aeolicus (LeuT Aa ) [7] opened the possibility of understanding the structurefunction relationship for this important transporter family.…”

Section: Introductionmentioning

confidence: 99%

Generation of a 3D model for human GABA transporter hGAT-1 using molecular modeling and investigation of the binding of GABA

Wein

Wanner

2009

J Mol Model

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A three-dimensional model of the human Na+/Cl--dependent y-aminobutyric acid (GABA) transporter hGAT-1 was developed by homology modeling and refined by subsequent molecular modeling using the crystal structure of a bacterial homologue leucine transporter from Aquifex aeolicus (LeuTAa) as the template. Protein structure quality checks show that the resulting structure is particular suited for the analysis of the substrate binding pocket and virtual screening experiments. Interactions of GABA and the substrate binding pocket were investigated using docking studies. The difference of 6 out of 13 substrate interacting side chains between hGAT-1 and LeuTAa lead to the different substrate preference which can be explained using our three-dimensional model of hGAT-1. In particular the replacement of serine 256 and isoleucine 359 in LeuTAa with glycine and threonine in hGAT-1 seems to facilitate the selection of GABA as the main substrate by changing the hydrogen bonding pattern in the active site to the amino group of the substrate. For a set of 12 compounds flexible docking experiments were performed using LigandFit in combination with the Jain scoring function. With few exceptions the obtained rank order of potency was in line with experimental data. Thus, the method can be assumed to give at least a rough estimate of the potency of potential of GABA uptake inhibitors Response to Reviewers: Reviewer #2: Obviously, no PME was used for Gromacs minimization, which is not state-of-the-art.Answer to reviewer: We are very thankful for this suggestion and have repeated the procedure of minimizing the initial protein structure using PME. In addition, we have heated the system using a simulated annealing approach in order to let the protein structure adopt better to GABA as the ligand. The differences in the resulting structure compared to the original structure are very small but, of course, in the paper we report the structure modelled with PME and after simujlated annealing.Reviewer #2:I doubt that LigandFit is the only one of the docking codes mentioned which is able to cope with the sodium-carboxylate-interaction mentioned in the text. the pose of the bound leucine in the leucine transporter LeuTAa showed that LigandFit was the best software to reproduce the orientation of the leucine in the active site and especially the interaction of the Leucine carboxyl group with the sodium atom Na1." In order to select the best-suited docking software for our needs, we have done preliminary docking calculations using the X-Ray structure of LeuTaa. These calculations showed clearly that LigandFit was best suited to reproduce especially the important interaction of the carboxylate to the sodium atom (Na1). Even with modifications in parameter files suggested by support people for FlexX and GOLD, LigandFit performed better in this very special case! And, differrent to the Pallo publication we don't need to introduce the carboxy-sodium interaction as restraint for our calculations! Reviewer #2: The much more extens...

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“…DAT is a member of high affinity sodium-(Na + ) and chloride (Cl − )-dependent SLC6 transporter gene family, which also includes transporters for neurotransmitters serotonin (5-HT), norepinephrine (NE), γ-amino butyric acid (GABA) and glycine Gether et al, 2006). All members of the family share a similar predicted topology of twelve transmembrane domains, cytoplasmic amino-and carboxy-terminals, a large second extracellular loop with multiple N-linked glycosylation sites, and cytoplasmic phosphorylation sites.…”

Section: Introductionmentioning

confidence: 99%

Dopamine transporter endocytic determinants: Carboxy terminal residues critical for basal and PKC-stimulated internalization

Boudanova

Navaroli

Stevens

et al. 2008

Molecular and Cellular Neuroscience

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Dopamine (DA) reuptake terminates dopaminergic neurotransmission and is mediated by DA transporters (DATs). Acute protein kinase C (PKC) activation accelerates DAT internalization rates, thereby reducing DAT surface expression. Basal DAT endocytosis and PKC-stimulated DAT functional downregulation rely on residues within the 587-596 region, although whether PKCinduced DAT downregulation reflects transporter endocytosis mechanisms linked to those controlling basal endocytosis rates is unknown. Here, we define residues governing basal and PKCstimulated DAT endocytosis. Alanine substituting DAT residues 587-590 1) abolished PKC stimulation of DAT endocytosis, and 2) markedly accelerated basal DAT internalization, comparable to that of wildtype DAT during PKC activation. Accelerated basal DAT internalization relied specifically on residues 588-590, which are highly conserved among SLC6 neurotransmitter transporters. Our results support a model whereby residues within the 587-590 stretch may serve as a locus for a PKC-sensitive braking mechanism that tempers basal DAT internalization rates.

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Neurotransmitter transporters: molecular function of important drug targets

Cited by 295 publications

References 67 publications

Molecular Targets for Antiepileptic Drug Development

Molecular Targets for Antiepileptic Drug Development

Generation of a 3D model for human GABA transporter hGAT-1 using molecular modeling and investigation of the binding of GABA

Dopamine transporter endocytic determinants: Carboxy terminal residues critical for basal and PKC-stimulated internalization

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