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Neurotransmitter Transporters (neurotransmitter + transporter)
Selected AbstractsNeurotransmitter transporters and their impact on the development of psychopharmacologyBRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2006Leslie Iversen The synaptic actions of most neurotransmitters are inactivated by reuptake into the nerve terminals from which they are released, or by uptake into adjacent cells. A family of more than 20 transporter proteins is involved. In addition to the plasma membrane transporters, vesicular transporters in the membranes of neurotransmitter storage vesicles are responsible for maintaining vesicle stores and facilitating exocytotic neurotransmitter release. The cell membrane monoamine transporters are important targets for CNS drugs. The transporters for noradrenaline and serotonin are key targets for antidepressant drugs. Both noradrenaline-selective and serotonin-selective reuptake inhibitors are effective against major depression and a range of other psychiatric illnesses. As the newer drugs are safer in overdose than the first-generation tricyclic antidepressants, their use has greatly expanded. The dopamine transporter (DAT) is a key target for amphetamine and methylphenidate, used in the treatment of attention deficit hyperactivity disorder. Psychostimulant drugs of abuse (amphetamines and cocaine) also target DAT. The amino-acid neurotransmitters are inactivated by other families of neurotransmitter transporters, mainly located on astrocytes and other non-neural cells. Although there are many different transporters involved (four for GABA; two for glycine/D -serine; five for L -glutamate), pharmacology is less well developed in this area. So far, only one new amino-acid transporter-related drug has become available: the GABA uptake inhibitor tiagabine as a novel antiepileptic agent. British Journal of Pharmacology (2006) 147, S82,S88. doi:10.1038/sj.bjp.0706428 [source] Upregulation of Serotonin Transporter by Alcohol in Human Dendritic Cells: Possible Implication in Neuroimmune DeregulationALCOHOLISM, Issue 10 2009Dakshayani Kadiyala Babu Background:, Alcohol is the most widely abused substance and its chronic consumption causes neurobehavioral disorders. It has been shown that alcohol affects the function of immune cells. Dendritic cells (DC) serve as the first line of defense against infections and are known to accumulate neurotransmitters such as 5-hydroxytryptamine (5-HT). The enzyme monoamine oxidase-A (MAO-A) degrades 5-HT that is associated with clinical depression and other neurological disorders. 5-HT is selectively transported into neurons through the serotonin transporter (SERT), which is a member of the sodium- and chloride-dependent neurotransmitter transporter (SLC6) family. SERT also serves as a receptor for psychostimulant recreational drugs. It has been demonstrated that several drugs of abuse such as amphetamine and cocaine inhibit the SERT expression; however, the role of alcohol is yet to be elucidated. We hypothesize that alcohol can modulate SERT and MAO-A expression in DC, leading to reciprocal downregulation of 5-HT in extracellular medium. Methods:, Dendritic cells were treated with different concentrations (0.05% to 0.2%v/v) of alcohol for 24,72 hours and processed for SERT and MAO-A expression using Q-PCR and Western blots analysis. In addition, SERT function in DC treated with alcohol both in the presence and absence of imipramine, a SERT inhibitor was measured using 4-[4-(dimethylamino)styryl]-1-methylpyridinium iodide uptake assay. 5-HT levels in culture supernatant and intracellular 5-hydroxy indole acetic acid (5-HIAA) and cyclic AMP were also quantitated using ELISA. Results:, Dendritic cells treated with 0.1% alcohol for 24 hours showed significant upregulation of SERT and MAO-A expression compared with untreated DC. We also observed that 0.1% alcohol enhanced the function of SERT and decreased extracellular 5-HT levels compared with untreated DC cultures, and this was associated with the elevation of intracellular 5-HIAA and cyclic AMP levels. Conclusions:, Our study suggests that alcohol upregulates SERT and MAO-A by elevating cyclic AMP, which may lead to decreased concentration of 5-HT in the extracellular medium. As 5-HT is a major neurotransmitter and an inflammatory mediator, its alcohol-mediated depletion may cause both neurological and immunological deregulation. [source] Association of SLC6A12 variants with aspirin-intolerant asthma in a Korean populationANNALS OF HUMAN GENETICS, Issue 4 2010Charisse Flerida A. Pasaje Summary Aspirin-intolerant asthma (AIA) occurs from asthma exacerbation after exposure to aspirin. However, the underlying mechanisms of AIA occurrence are still unclear. The critical role of the solute carrier family 6 (neurotransmitter transporter, betaine/GABA) member 12 (SLC6A12) gene in GABAergic transmission, which is associated with mucus production in asthma, makes it a candidate gene for AIA association study. Eight single nucleotide polymorphisms (SNPs) in SLC6A12 were genotyped in 163 aspirin-intolerant asthma (AIA) and 429 aspirin-tolerant asthma (ATA) patients of Korean ethnicity. Associations between polymorphisms of SLC6A12 and AIA were analysed using multivariate logistic analysis. Results showed that two polymorphisms and a haplotype in SLC6A12, rs499368 (P= 0.005; Pcorr= 0.03), rs557881 (non-synonymous C10R, P= 0.007; Pcorr= 0.04), and SLC6A12_BL1_ht1 (P= 0.009; Pcorr= 0.05) respectively, were significantly associated with AIA after multiple testing corrections. In addition, SNPs of SLC6A12 were significantly associated with the fall rate of FEV1 by aspirin provocation suggesting that SLC6A12 could affect reversibility of lung function abnormalities in AIA patients. Although these results are preliminary and future replications are needed to confirm these findings, this study showed evidence of association between variants in SLC6A12 and AIA occurrence among asthmatics in a Korean population. [source] A screen for neurotransmitter transporters expressed in the visual system of Drosophila melanogaster identifies three novel genesDEVELOPMENTAL NEUROBIOLOGY, Issue 5 2007Rafael Romero-Calderón Abstract The fly eye provides an attractive substrate for genetic studies, and critical transport activities for synaptic transmission and pigment biogenesis in the insect visual system remain unknown. We therefore screened for transporters in Drosophila melanogaster that are down-regulated by genetically ablating the eye. Using a large panel of transporter specific probes on Northern blots, we identified three transcripts that are down-regulated in flies lacking eye tissue. Two of these, CG13794 and CG13795, are part of a previously unknown subfamily of putative solute carriers within the neurotransmitter transporter family. The third, CG4476, is a member of a related subfamily that includes characterized nutrient transporters expressed in the insect gut. Using imprecise excision of a nearby transposable P element, we have generated a series of deletions in the CG4476 gene. In fast phototaxis assays, CG4476 mutants show a decreased behavioral response to light, and the most severe mutant behaves as if it were blind. These data suggest an unforeseen role for the "nutrient amino acid transporter" subfamily in the nervous system, and suggest new models to study transport function using the fly eye. © 2007 Wiley Periodicals, Inc. Develop Neurobiol, 2007 [source] VSD: A database for schizophrenia candidate genes focusing on variations,HUMAN MUTATION, Issue 1 2004Min Zhou Abstract Schizophrenia is a common mental disease characterized by delusions, hallucinations, and formal thought disorder. It has been demonstrated with genetic evidence that the disease is a polygenic disorder. Pharmacological, neurochemical, and clinical studies have suggested a number of schizophrenia susceptibility loci. In order to systematically search for genes with small effect in the development of schizophrenia, a database called VSD was established to provide variation data for publicly available candidate genes. Most of the genes encode neurotransmitter receptors, neurotransmitter transporters, and the enzymes involved in their metabolism. Other candidate genes extracted from published literature are also included. The variation information has been collected from publicly available mutation and polymorphism databases such as dbSNP, HGVbase, and OMIM, with single nucleotide polymorphism (SNP) being the most abundant form of collected variations. Reference sequences from NCBI's RefSeq database are used as references when positioning variation at transcript and protein levels. The nonsynonymous SNPs (nsSNPs) that lead to amino acid changes in the functional sites or domains of proteins are distinguished since they are more likely to affect protein function and would be target SNPs for association studies. In addition to variation data, gene descriptions, enzyme information, and other biological information for each gene locus are also included. The latest version of VSD contains 23,648 variations assigned to a total of 186 genes. Five-hundred eighty-eight domains and sites annotated in the SWISS-PROT and InterPro databases are found to contain nsSNPs. VSD may be accessed via the World Wide Web (www.chgb.org.cn/vsd.htm) and will be developed as an up-to-date and comprehensive locus-specific resource for identifying susceptibility genes for schizophrenia. Hum Mutat 23:1,7, 2004. © 2003 Wiley-Liss, Inc. [source] Constitutive high-affinity choline transporter endocytosis is determined by a carboxyl-terminal tail dileucine motifJOURNAL OF NEUROCHEMISTRY, Issue 1 2005Fabiola M. Ribeiro Abstract Maintenance of acetylcholine synthesis depends on the effective functioning of a high-affinity sodium-dependent choline transporter (CHT1). Recent studies have shown that this transporter is predominantly localized inside the cell, unlike other neurotransmitter transporters, suggesting that the trafficking of CHT1 to and from the plasma membrane may play a crucial role in regulating choline uptake. Here we found that CHT1 is rapidly and constitutively internalized in clathrin-coated vesicles to Rab5-positive early endosomes. CHT1 internalization is controlled by an atypical carboxyl-terminal dileucine-like motif (L531, V532) which, upon replacement by alanine residues, blocks CHT1 internalization in both human embryonic kidney 293 cells and primary cortical neurons and results in both increased CHT1 cell surface expression and choline transport activity. Perturbation of clathrin-mediated endocytosis with dynamin-I K44A increases cell surface expression and transport activity to a similar extent as mutating the dileucine motif, suggesting that we have identified the motif responsible for constitutive CHT1 internalization. Based on the observation that the localization of CHT1 to the plasma membrane is transient, we propose that acetylcholine synthesis may be influenced by processes that lead to the attenuation of constitutive CHT1 endocytosis. [source] Regulated trafficking of neurotransmitter transporters: common notes but different melodiesJOURNAL OF NEUROCHEMISTRY, Issue 1 2002Michael B. Robinson Abstract The activity of biogenic amine and amino acid neurotransmitters is limited by presynaptic and astrocytic Na+ -dependent transport systems. Their functional importance is underscored by the observation that these transporters are the targets of broad classes of psychotherapeutic agents, including antidepressants and stimulants. Early studies suggested that the activity of these transporters can be fine tuned by a number of different signaling pathways. In the past five years, several groups have provided compelling evidence that changing the cell surface availability of these transporters contributes to this fine tuning. This regulated trafficking can result in rapid (within minutes) increases or decreases in the plasma membrane expression of these transporters and is independent of transcriptional or translational control mechanisms. Many of the same signaling molecules, including protein kinase C (PKC), tyrosine kinase, phosphatidylinositol 3-kinase (P13-K), and protein phosphatase, regulate the transporters for different neurotransmitters. In addition to these classical receptor activated pathways, transporter substrates also regulate activity and cell surface expression of these transporters. In fact, some of the transporters form complexes with signaling molecules. Given the functional and genetic similarities of these transporters, it is not surprising that the same signaling molecules regulate their trafficking, but except for the molecules, the actual effects on individual transporters are remarkably different. It,is as if the same musical notes have been rearranged into several different melodies. [source] Effect of DOV 102,677 on the Volitional Consumption of Ethanol by Myers' High Ethanol-Preferring RatALCOHOLISM, Issue 11 2007Brian A. McMillen Background:, Inhibitors of monoamine neurotransmitter transporters are well established as antidepressants. However, the evidence that single (serotonin) or dual (serotonin,norepinephrine) neurotransmitter uptake inhibitors can treat ethanol abuse, either as a comorbidity with depression or as a separate entity, is inconsistent. Drugs that have, in addition, the ability to inhibit dopamine uptake may have an advantage in the treatment of alcohol abuse. Therefore, the inhibitor of norepinephrine, serotonin and dopamine uptake, DOV 102,677, was tested for its effects on the volitional consumption of ethanol by an ethanol-preferring rat strain. Methods:, Myers' high ethanol-preferring rats were screened by a 10-day, 3 to 30% step-up test and then given free access to the preferred concentration of ethanol in a 3-bottle choice task. Consumption of ethanol (g/kg), water, food, and body weight were measured daily during a 3-day predrug treatment period, a 3-day treatment period, and a 3-day posttreatment period. Additional Sprague,Dawley rats were observed for 24 hours for the behavioral effects of 2.0 mg/kg s.c. reserpine after a 30-minute pretreatment with different doses of DOV 102,677. Results:, The triple monoamine uptake inhibitor DOV 102,677 dose-dependently decreased the volitional consumption of ethanol by as much as 71.2% (20 mg/kg i.p., b.i.d.) over 3 days of administration. This effect carried over into the posttreatment period. Similarly, the proportion of ethanol to total fluids consumed declined by 66.2% (20 mg/kg s.c., b.i.d.), while food consumption and body weight were unaltered. In contrast, amperozide (2 mg/kg i.p., b.i.d.) suppressed the amount of ethanol consumed by 56%, while naltrexone (5 mg/kg i.p., b.i.d.) was without effect. DOV 102,677 (40 mg/kg s.c.) inhibited reserpine-induced akinesia and ptosis, but not hypothermia in Sprague,Dawley rats, consistent with its transient inhibition of serotonin transport, and more long-lived inhibition of norepinephrine and dopamine uptake. Conclusions:, DOV 102,677 significantly decreased the volitional consumption of ethanol with minimal alterations in the intake of food or on body weight in an ethanol-preferring rat strain, suggesting that triple reuptake inhibitors may find utility in treating alcohol abuse. [source] Neurotransmitter transporters and their impact on the development of psychopharmacologyBRITISH JOURNAL OF PHARMACOLOGY, Issue S1 2006Leslie Iversen The synaptic actions of most neurotransmitters are inactivated by reuptake into the nerve terminals from which they are released, or by uptake into adjacent cells. A family of more than 20 transporter proteins is involved. In addition to the plasma membrane transporters, vesicular transporters in the membranes of neurotransmitter storage vesicles are responsible for maintaining vesicle stores and facilitating exocytotic neurotransmitter release. The cell membrane monoamine transporters are important targets for CNS drugs. The transporters for noradrenaline and serotonin are key targets for antidepressant drugs. Both noradrenaline-selective and serotonin-selective reuptake inhibitors are effective against major depression and a range of other psychiatric illnesses. As the newer drugs are safer in overdose than the first-generation tricyclic antidepressants, their use has greatly expanded. The dopamine transporter (DAT) is a key target for amphetamine and methylphenidate, used in the treatment of attention deficit hyperactivity disorder. Psychostimulant drugs of abuse (amphetamines and cocaine) also target DAT. The amino-acid neurotransmitters are inactivated by other families of neurotransmitter transporters, mainly located on astrocytes and other non-neural cells. Although there are many different transporters involved (four for GABA; two for glycine/D -serine; five for L -glutamate), pharmacology is less well developed in this area. So far, only one new amino-acid transporter-related drug has become available: the GABA uptake inhibitor tiagabine as a novel antiepileptic agent. British Journal of Pharmacology (2006) 147, S82,S88. doi:10.1038/sj.bjp.0706428 [source] | |||||||||||||