Human dopamine transporter gene variation: effects of protein coding variants V55A and V382A on expression and uptake activities

Lin, Zhicheng; Uhl, George R.

doi:10.1038/sj.tpj.6500169

Cited by 30 publications

(12 citation statements)

References 38 publications

(43 reference statements)

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“…Recent findings by Lin and Uhl [66] supported the notion that individuals with DAT variants could display altered dopaminergic function. They defined DAT mutants, V55A in cytoplasmic N-terminal domain and V382A in the putative forth extracellular loop (ECL), in in vitro COS cell transient expression system.…”

Section: Naturally Occurring Mutantsmentioning

confidence: 83%

Inhibition of Monoamine Neurotransmitter Transporters and Central Nervous System Stimulation Induced by Synthetic Local Anesthetics and Cocaine: A Comparative Review-Update

Dohi¹,

Kitayama²,

Morita³

2005

CMCCNSA

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Monoamine transporters (MAT) are the target molecules of cocaine for induction of its central stimulating effect, resultant reward. Sensitization of central nervous system stimulation by cocaine is produced by intermittent use of cocaine and typically appears in behavioral hyperactivity in animals. Na + channels are other important molecules for induction of seizures of cocaine in abuse. The mechanisms for the expression of seizures and development of cocaine kindling by repeated cocaine intake may include the facilitation by inhibition of MAT of seizures induced by γ-aminobutyric acid obstacle-related mechanism resulting from an inhibition of Na + channels on the nerve by cocaine.Various molecular biological techniques have been utilized to investigate the structure-function relationship of MAT molecules and revealed multiple molecular determinates on MAT molecules for critical interaction with cocaine. The evidence would help to understand the molecular interaction of MAT and cocaine, leading to the development of medication for cocaine reward and kindling.

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Section: Naturally Occurring Mutantsmentioning

confidence: 83%

Inhibition of Monoamine Neurotransmitter Transporters and Central Nervous System Stimulation Induced by Synthetic Local Anesthetics and Cocaine: A Comparative Review-Update

Dohi¹,

Kitayama²,

Morita³

2005

CMCCNSA

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“…Indeed, two functional SNPs shown to influence transcriptional efficiency-DRD2 2141 ins/del (Arinami et al, 1997) and DRD2 C957T (Duan et al, 2003)-may also affect bupropion efficacy and, ideally, should be considered in future exploration of DRD26 bupropion interactions on smoking cessation. Furthermore, even though the SLC6A3 39 VNTR does not appear to affect expression of the transporter in vitro (Greenwood & Kelsoe, 2003;Mill, Asherson, Craig, & D'Souza, 2005), other SNPs and mutations do appear to influence dopamine transporter expression (Horschitz, Hummerich, Lau, Rietschel, & Schloss, 2005;Kelada et al, 2005;Lin & Uhl, 2003). This observation may account in part for the lack of replication in studies of associations between smoking phenotypes and the SLC6A3 39 VNTR polymorphism (Bierut et al, 2000;Jorm et al, 2000;Lerman et al, 1999;Sabol et al, 1999;Vandenbergh et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation

David

Brown

Papandonatos

et al. 2007

CNTR

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This randomized, double-blinded, placebo-controlled trial examined genetic influences on treatment response to sustained-release bupropion for smoking cessation. Smokers of European ancestry (N = 291), who were randomized to receive bupropion or placebo (12 weeks) plus counseling, were genotyped for the dopamine D2 receptor (DRD2-Taq1A), dopamine transporter (SLC6A3 3' VNTR), and cytochrome P450 2B6 (CYP2B6 1459 CT) polymorphisms. Main outcome measures were cotinine-verified point prevalence of abstinence at end of treatment and at 2-, 6-, and 12-month follow-ups post quit date. Using generalized estimating equations, we found that bupropion, compared with placebo, was associated with significantly greater odds of abstinence at all time points (all p values<.01). We found a significant DRD2 x bupropion interaction (B = 1.49, SE = 0.59, p = .012) [corrected] and a three-way DRD2 x bupropion x craving interaction on 6-month smoking cessation outcomes (B = -0.45, SE = 0.22, p = .038), such that smokers with the A2/A2 genotype demonstrated the greatest craving reduction and the highest abstinence rates with bupropion. Furthermore, there was a significant DRD2 x CYP2B6 interaction (B = 1.43, SE = 0.56, p = .01), such that individuals with the DRD2-Taq1 A2/A2 genotype demonstrated a higher odds of abstinence only if they possessed the CYP2B6 1459 T/T or C/T genotype. Because the sample size of this study was modest for pharmacogenetic investigations, the results should be interpreted with caution. Although these results require replication, the data suggest preliminarily that the DRD2-Taq1A polymorphism may influence treatment response to bupropion for smoking cessation and, further, that exploration of gene x gene and gene x craving interactions in future, larger studies may provide mechanistic insights into the complex pharmacodynamics of bupropion.

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“…Dopamine uptake velocity and cocaine analog binding were reduced by half with the 1246C (382Ala) allele in transient expression assays, whereas the 265C (55Ala) allele had 1.7-fold lower K m for dopamine uptake (Lin and Uhl, 2003).…”

Section: Dopamine Transporter Gene (Slc6a3)mentioning

confidence: 93%

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

et al. 2005

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Human dopamine transporter gene variation: effects of protein coding variants V55A and V382A on expression and uptake activities

Cited by 30 publications

References 38 publications

Inhibition of Monoamine Neurotransmitter Transporters and Central Nervous System Stimulation Induced by Synthetic Local Anesthetics and Cocaine: A Comparative Review-Update

Inhibition of Monoamine Neurotransmitter Transporters and Central Nervous System Stimulation Induced by Synthetic Local Anesthetics and Cocaine: A Comparative Review-Update

Pharmacogenetic clinical trial of sustained-release bupropion for smoking cessation

Pharmacogenetics and Human Molecular Genetics of Opiate and Cocaine Addictions and Their Treatments

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