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The SLC6 transporters: perspectives on structure, functions, regulation, and models for transporter dysfunction.
Rudnick G, Krämer R, Blakely RD, Murphy DL, Verrey F
(2014) Pflugers Arch 466: 25-42
MeSH Terms: Amino Acid Sequence, Animals, GABA Plasma Membrane Transport Proteins, Humans, Ion Transport, Molecular Sequence Data
Show Abstract · Added February 12, 2015
The human SLC6 family is composed of approximately 20 structurally related symporters (co-transporters) that use the transmembrane electrochemical gradient to actively import their substrates into cells. Approximately half of the substrates of these transporters are amino acids, with others transporting biogenic amines and/or closely related compounds, such as nutrients and compatible osmolytes. In this short review, five leaders in the field discuss a number of currently important research themes that involve SLC6 transporters, highlighting the integrative role they play across a wide spectrum of different functions. The first essay, by Gary Rudnick, describes the molecular mechanism of their coupled transport which is being progressively better understood based on new crystal structures, functional studies, and modeling. Next, the question of multiple levels of transporter regulation is discussed by Reinhard Krämer, in the context of osmoregulation and stress response by the related bacterial betaine transporter BetP. The role of selected members of the human SLC6 family that function as nutrient amino acid transporters is then reviewed by François Verrey. He discusses how some of these transporters mediate the active uptake of (essential) amino acids into epithelial cells of the gut and the kidney tubule to support systemic amino acid requirements, whereas others are expressed in specific cells to support their specialized metabolism and/or growth. The most extensively studied members of the human SLC6 family are neurotransmitter reuptake transporters, many of which are important drug targets for the treatment of neuropsychiatric disorders. Randy Blakely discusses the role of posttranscriptional modifications of these proteins in regulating transporter subcellular localization and activity state. Finally, Dennis Murphy reviews how natural gene variants and mouse genetic models display consistent behavioral alterations that relate to altered extracellular neurotransmitter levels.
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6 MeSH Terms
Alterations in GABA-related transcriptome in the dorsolateral prefrontal cortex of subjects with schizophrenia.
Hashimoto T, Arion D, Unger T, Maldonado-Avilés JG, Morris HM, Volk DW, Mirnics K, Lewis DA
(2008) Mol Psychiatry 13: 147-61
MeSH Terms: Adult, Aged, Animals, Antipsychotic Agents, Benzodiazepines, Case-Control Studies, Chloroquinolinols, Female, GABA Plasma Membrane Transport Proteins, Gene Expression Regulation, Glutamate Decarboxylase, Humans, Macaca fascicularis, Male, Middle Aged, Neuropeptides, Olanzapine, Oligonucleotide Array Sequence Analysis, Prefrontal Cortex, Protein Subunits, Receptors, GABA-A, Schizophrenia
Show Abstract · Added May 19, 2014
In subjects with schizophrenia, impairments in working memory are associated with dysfunction of the dorsolateral prefrontal cortex (DLPFC). This dysfunction appears to be due, at least in part, to abnormalities in gamma-aminobutyric acid (GABA)-mediated inhibitory circuitry. To test the hypothesis that altered GABA-mediated circuitry in the DLPFC of subjects with schizophrenia reflects expression changes of genes that encode selective presynaptic and postsynaptic components of GABA neurotransmission, we conducted a systematic expression analysis of GABA-related transcripts in the DLPFC of 14 pairs of schizophrenia and age-, sex- and post-mortem interval-matched control subjects using a customized DNA microarray with enhanced sensitivity and specificity. Subjects with schizophrenia exhibited expression deficits in GABA-related transcripts encoding (1) presynaptic regulators of GABA neurotransmission (67 kDa isoform of glutamic acid decarboxylase (GAD(67)) and GABA transporter 1), (2) neuropeptides (somatostatin (SST), neuropeptide Y (NPY) and cholecystokinin (CCK)) and (3) GABA(A) receptor subunits (alpha1, alpha4, beta3, gamma2 and delta). Real-time qPCR and/or in situ hybridization confirmed the deficits for six representative transcripts tested in the same pairs and in an extended cohort, respectively. In contrast, GAD(67), SST and alpha1 subunit mRNA levels, as assessed by in situ hybridization, were not altered in the DLPFC of monkeys chronically exposed to antipsychotic medications. These findings suggest that schizophrenia is associated with alterations in inhibitory inputs from SST/NPY-containing and CCK-containing subpopulations of GABA neurons and in the signaling via certain GABA(A) receptors that mediate synaptic (phasic) or extrasynaptic (tonic) inhibition. In concert with previous findings, these data suggest that working memory dysfunction in schizophrenia is mediated by altered GABA neurotransmission in certain DLPFC microcircuits.
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22 MeSH Terms
Sequence variation in the human dopamine transporter gene in children with attention deficit hyperactivity disorder.
Mazei-Robison MS, Couch RS, Shelton RC, Stein MA, Blakely RD
(2005) Neuropharmacology 49: 724-36
MeSH Terms: Adolescent, Alanine, Alleles, Attention Deficit Disorder with Hyperactivity, Child, Cohort Studies, Dopamine Plasma Membrane Transport Proteins, Electrophoresis, Capillary, Exons, Family Health, Female, GABA Plasma Membrane Transport Proteins, Gene Frequency, Genetic Variation, Genotype, Humans, Male, Minisatellite Repeats, Polymorphism, Genetic, RNA, Messenger, Retrospective Studies, Reverse Transcriptase Polymerase Chain Reaction, Valine
Show Abstract · Added July 10, 2013
The activity of the presynaptic dopamine (DA) transporter (DAT) is critical in mediating the magnitude and duration of dopaminergic signaling in the brain. Multiple genetic studies have found an association between attention deficit hyperactivity disorder (ADHD) and a variable number tandem repeat (VNTR) in the 3'-untranslated region (3'VNTR) of the hDAT gene (SLC6A3), however none of these studies examined the hDAT coding region for polymorphisms. Thus, we sought evidence of polymorphisms in hDAT, focusing on the coding region and splice junctions, utilizing genomic DNA from children diagnosed with ADHD. Two separate ADHD cohorts (N=70 and N=42) were screened and sampled for both status of the 3'VNTR and for common/novel genomic variants. We found evidence of increased DAT variation in African-American subjects as well as in predominantely hyperactive-impulsive probands. Cumulatively, multiple hDAT sequence variants were identified, including five novel variants, as well as one nonsynonymous single nucleotide polymorphism (SNP), converting Ala559 to Val (A559V). A559V was identified in two Caucasian male siblings with ADHD and both subjects were homozygous for the ADHD-associated, 10-repeat 3'VNTR allele. Interestingly, the A559V variant was previously identified in a subject with bipolar disorder [. Molecular Psychiatry 5, 275], a psychiatric disorder that has a significant number of overlapping symptoms with ADHD.
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23 MeSH Terms
SNARE-ing neurotransmitter transporters.
Blakely RD, Sung U
(2000) Nat Neurosci 3: 969-71
MeSH Terms: Animals, Antigens, Surface, Carrier Proteins, GABA Plasma Membrane Transport Proteins, Humans, Membrane Proteins, Membrane Transport Proteins, Nerve Tissue Proteins, Neurotransmitter Agents, Organic Anion Transporters, SNARE Proteins, Synaptic Transmission, Syntaxin 1, Vesicular Transport Proteins
Added July 10, 2013
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14 MeSH Terms
Sodium-dependent GABA-induced currents in GAT1-transfected HeLa cells.
Risso S, DeFelice LJ, Blakely RD
(1996) J Physiol 490 ( Pt 3): 691-702
MeSH Terms: Animals, Carrier Proteins, Cells, Cultured, Dose-Response Relationship, Drug, GABA Plasma Membrane Transport Proteins, HeLa Cells, Humans, Membrane Potentials, Membrane Proteins, Membrane Transport Proteins, Organic Anion Transporters, Rats, Sodium, Time Factors, Transfection, gamma-Aminobutyric Acid
Show Abstract · Added July 10, 2013
1. HeLa cells were infected with recombinant vaccinia virus containing the T7 RNA polymerase gene and transfected with the cDNA for a rat GABA transporter, GAT1, cloned downstream of a T7 RNA polymerase promoter. Six to sixteen hours after transfection, whole-cell recording with a voltage ramp in the range -90 to 50 mV revealed GABA-induced currents (approximately -100 pA at -60 mV in 100 microM GABA, 16 h after transfection at room temperature). No GABA-induced currents were observed in parental HeLa cells or in mock-transfected cells. 2. GABA-induced currents were suppressed by extracellular perfusion with GABA-free solutions or addition of GAT1 inhibitors SKF89976-A or SKF100330-A. At fixed voltage the GABA dependence of the inward current fitted the Michaelis-Menten equation with a Hill coefficient, n, near unity and an equilibrium constant, K(m), near 3 microM. The Na+ dependence of the inward currents fitted the Michaelis-Menten equation with n approximately equal to 2 and K(m) approximately equal to 10 mM. The constants n and K(m) for GABA and Na+ were independent of voltage in the range -90 to -30 mV. 3. GABA-induced currents reverse direction in the range 5-10 mV. The implication of this result is that GAT1 can mediate electrogenic (electrophoretic) influx or efflux of GABA depending on the membrane voltage. The presence of an outward current in our experiments is consistent with radioactive-labelled flux data from resealed vesicle studies. However, it is inconsistent with frog oocyte expression experiments using the sample clone. In oocytes, GAT1 generates no outward current in a similar voltage range. Smaller intracellular volume or higher turnover rates in the mammalian expression system may explain the outward currents. 4. External GABA induces inward current, and internal GABA induces outward current. However, in cells initially devoid of internal GABA, external GABA can also facilitate an outward current. This GAT1-mediated outward current occurs only after applying negative potentials to the cell. These data are consistent with the concept that negative potentials drive GABA and Na+ into the cell, which then leads to electrogenic efflux through GAT1 at positive voltages. 5. Assuming coupled transport, we estimate the number of transporters, N, times the turnover rate, r, to be Nr approximately 10(9) s-1 under nominal conditions (V = -60 mV, 30 microM GABA, 130 mM Na+ and room temperature). This indicates either very high levels of expression (approximately 10(4) microns-2), assuming published turnover rates (approximately 10 s-1), or turnover rates that are significantly greater than previously reported. As an alternative, a channel may exist in the GAT1 protein that is gated by GABA and Na+ and blocked by GAT1 antagonists. The channel mode of conduction would exist in addition to the coupled, fixed-stoichiometry transporter mode of conduction.
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16 MeSH Terms
Functional expression and CNS distribution of a beta-alanine-sensitive neuronal GABA transporter.
Clark JA, Deutch AY, Gallipoli PZ, Amara SG
(1992) Neuron 9: 337-48
MeSH Terms: Amino Acid Sequence, Animals, Base Sequence, Brain Chemistry, Carrier Proteins, Chlorides, DNA, GABA Plasma Membrane Transport Proteins, Gene Expression, Humans, Male, Membrane Proteins, Membrane Transport Proteins, Molecular Sequence Data, Nerve Tissue Proteins, Neuroglia, Neurons, Nucleic Acid Hybridization, Organic Anion Transporters, RNA, Messenger, Rats, Rats, Inbred Strains, Sodium, Tissue Distribution, beta-Alanine
Show Abstract · Added May 27, 2014
The synaptic action of gamma-aminobutyric acid (GABA) is terminated by high affinity, Na(+)-dependent transport processes in both neurons and glia. We have isolated a novel GABA transporter cDNA, GAT-B, which encodes a high affinity (Km = 2.3 microM), Na(+)- and Cl(-)-dependent GABA transport protein that is potently blocked by beta-alanine, a compound generally considered a selective inhibitor of glial transport. However, in situ hybridization studies indicate that GAT-B mRNA is expressed predominantly within neurons. These data indicate that the neuronal-glial distinction of GABA transporters based on inhibitor sensitivities must be reconsidered and suggest a greater diversity of GABA transporters than has been predicted by previous pharmacologic studies.
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25 MeSH Terms