Neurotransmitter transporters: fruitful targets for CNS drug discovery

Iversen, Leslie L.

doi:10.1038/sj.mp.4000728

Cited by 135 publications

(91 citation statements)

References 23 publications

(23 reference statements)

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“…The DAT plays a critical role in modulating dopamine transmission by regulating dopamine availability in the synapse. 3,46,47 This precept has driven intensive investigation of variability in the DAT gene that may contribute to regulation of DAT expression, function and consequent pathological states. The discovery of a variable number of tandem repeat (VNTR) sequences in the 3Ј-UTR of the human DAT gene 25 led to widespread screening of populations to examine the frequency of the repeat sequences.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] By actively sequestering extracellular dopamine to intracellular compartments, the DAT plays a key role in adjusting dopamine availability and consequent dopamine-mediated behaviors. As dopamine is implicated in substance abuse and neuropsychiatric or neurodegenerative diseases, transporter levels and function may contribute to the etiology of or susceptibility to dopamine-related disorders.…”

Section: Introductionmentioning

confidence: 99%

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Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

2002

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

2002

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“…For co-immunoprecipitation from rat brain homogenates a polyclonal rabbit antiserum raised against the fourth extracellular loop of SERT, denoted anti-SERT(EL4), 3 was found to be most suitable. This antiserum was kindly provided by Dr. Christopher Tate, Medical Research Council Laboratory of Molecular Biology (Cambridge, UK).…”

Section: Methodsmentioning

confidence: 99%

“…SERT is of particular clinical and pharmacological interest as it has been implicated in a variety of neuropsychiatric disorders, as well as several dysfunctions in the periphery (1). It is the primary target for a number of widely prescribed antidepressants and is also the site of action for drugs of abuse (2,3), including methylenedioxymethamphetamine (MDMA, "ecstasy") and cocaine (4,5). SERT belongs to the SLC6 family of sodium-and chloride-dependent neurotransmitter transporters, which also include for example transporters for dopamine (DAT), norepinephrine (NET), ␥-aminobutyric acid (GAT), and glycine (GLYT1 and GLYT2) (6).…”

Section: The Serotonin Transporter (Sert)mentioning

confidence: 99%

Subcellular Redistribution of the Serotonin Transporter by Secretory Carrier Membrane Protein 2

Müller

Wiborg²,

Haase

2006

Journal of Biological Chemistry

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The serotonin transporter (SERT) belongs to the SLC6 family of sodium-and chloride-dependent neurotransmitter transporters responsible for uptake of amino acids and biogenic amines from extracellular spaces. Their activities and subcellular distributions are regulated by various cellular mechanisms, including interactions with other proteins. Using the yeast twohybrid approach we screened a human brain cDNA library and identified secretory carrier membrane protein 2 (SCAMP2) as a novel SERT-interacting protein. GST-pulldown assays confirmed the physical interaction between SCAMP2 and the N-terminal domain of SERT. In addition, SERT was found to form a complex with SCAMP2 as demonstrated by co-immunoprecipitation from a heterologous expression system and from rat brain homogenate. Co-expression of SERT and SCAMP2 in mammalian cells results in the subcellular redistribution of SERT with a decrease in cell surface SERT and a concomitant reduction in 5-HT uptake activity. Using confocal microscopy we show that in neuronal cells endogenous SERT co-localizes with SCAMP2 in discrete structures also containing the lipid raft marker flotillin-1 and the SNARE protein syntaxin 1A. In contrast, SERT immunoreactivity is clearly segregated from transferrin receptor-containing endosomes. A single amino acid mutation, cysteine-201 to alanine, within the conserved cytoplasmic E peptide of SCAMP2, abolished SCAMP2-mediated down-regulation of SERT, although this mutation had no effect on the physical interaction between SERT and SCAMP2. Taken together, our results suggest that SCAMP2 plays an important role in the regulation of the subcellular distribution of SERT.

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“…The medical relevance of these proteins is obvious; for instance, it has long been known that antidepressant drugs block the transporter for norepinephrine and serotonin (2). Likewise, tiagabine, an inhibitor of GABA transport, is used as an anticonvulsant in the treatment of epileptic seizures (3). Transporters support bidirectional flux of substrate, i.e.…”

Section: Namentioning

confidence: 99%

Mutations within an Intramembrane Leucine Heptad Repeat Disrupt Oligomer Formation of the Rat GABA Transporter 1

Scholze

Freissmuth

Sitte

2002

Journal of Biological Chemistry

109

134

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Na؉ /Cl ؊ -dependent neurotransmitter transporters form constitutive oligomers, the significance of which is not known. In soluble proteins, leucine heptad repeats drive dimerization; the rat ␥-aminobutyric acid transporter GAT-1 (rGAT) contains a motif reminiscent of a leucine heptad repeat in the second transmembrane helix (TM2). We substituted leucine residues in TM2 of rGAT by alanine and tested the ability of the resulting mutants to form oligomers by three methods of Fö rster resonance energy transfer (FRET) microscopy. Replacement of one leucine (L97A) resulted in considerable loss of energy transfer, replacing two or more ablated it completely. Furthermore, intracellular trapping increased with the number of leucine substitutions. Only rGAT-L97A reached the cell surface to a sufficient amount such that, in intact cells, it was indistinguishable from wild type rGAT with respect to substrate transport, binding of inhibitors, and regulation by protein kinase C. However, in membrane vesicles prepared from transfected cells, all mutants were still functional. In addition, FRET was readily detected during maturation of wild type rGAT, when the bulk of the protein resided in the endoplasmic reticulum. Hence, our findings strongly argue for a role of oligomer formation during biosynthesis and subsequent delivery of the multimer from the endoplasmic reticulum to the plasma membrane. Naϩ /Cl Ϫ -dependent neurotransmitter transporters (e.g. the transporters for dopamine, serotonin, or GABA) 1 retrieve neurotransmitters from the synaptic cleft into the presynaptic specialization (1). The medical relevance of these proteins is obvious; for instance, it has long been known that antidepressant drugs block the transporter for norepinephrine and serotonin (2). Likewise, tiagabine, an inhibitor of GABA transport, is used as an anticonvulsant in the treatment of epileptic seizures (3). Transporters support bidirectional flux of substrate, i.e. not only do they mediate influx of substrate but they also allow for non-exocytotic release of substrate (4). Compounds that induce reverse transport enjoy widespread popularity among illicit drug users; this is particularly true for amphetamine and its congeners, including ecstasy.Increasing evidence suggests that neurotransmitter transporters are oligomers (5, 6). Constitutive oligomerization has been visualized in intact cells by FRET microscopy (7); the oligomeric nature of neurotransmitter transporters has also been demonstrated by other, more disruptive, approaches, e.g. co-immunoprecipitation from detergent extracts and crosslinking (8 -10) and by freeze-fracture electron microscopy (11). However, the functional role of oligomer formation remains enigmatic. The hypothesis has been formulated that neurotransmitter transporters function in a manner analogous to ligand-gated ion channels, as binding of substrate induces an ion current (12-14). There is still an ongoing debate whether the GAT operates in a channel-like mode (15, 16) or according to the conservative "alternating ac...

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Neurotransmitter transporters: fruitful targets for CNS drug discovery

Cited by 135 publications

References 23 publications

Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

Polymorphisms in the 3′-untranslated region of human and monkey dopamine transporter genes affect reporter gene expression

Subcellular Redistribution of the Serotonin Transporter by Secretory Carrier Membrane Protein 2

Mutations within an Intramembrane Leucine Heptad Repeat Disrupt Oligomer Formation of the Rat GABA Transporter 1

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