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A Heils

Publications and source records attributed to A Heils.

42 records · Page 3Linked to original sources
PubMed1996

Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region.

Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

Adolescent↗
PubMed1996

The role of neurotransporters in excitotoxicity, neuronal cell death, and other neurodegenerative processes.

Neurotransporters are high-affinity transport proteins located in the plasma membrane of both presynaptic nerve and glial cells that mediate the removal of neurotransmitters from the synaptic cleft or represent intracellular transport systems that concentrate neurotransmitters in synaptic vesicles. They comprise three sub-groups, Na+/Cl- or Na+/K(+)-dependent cell surface transporters and H(+)-dependent transporters associated with synaptic vesicles. The new insights into neurotransporter diversity provide the means for novel approaches of studying neurotransmitter uptake processes at the molecular level, such as substrate translocation, antagonist binding, and regulation of gene expression, intracellular trafficking, and posttranslational modification. Moreover, modeling neurotransporter-related disorders and therapeutic strategies in genetically engineered animals are now feasible research strategies. Through an improved understanding of the modulation of neurotransporter function in the brain it may be possible to identify the molecular factors underlying the etiopathogenesis and pathophysiology of neurodegenerative disorders. Due to their specificity for distinct neuronal systems neurotransporters and their genes are potential targets for novel therapeutic strategies.

1-Methyl-4-phenylpyridinium↗
PubMed1996

Allelic variation of human serotonin transporter gene expression.

Mood, emotion, cognition, and motor functions as well as circadian and neuroendocrine rhythms, including food intake, sleep, and reproductive activity, are modulated by the midbrain raphe serotonin (5-HT) system. By directing the magnitude and duration of postsynaptic responses, carrier-facilitated 5-HT transport into and release from the presynaptic neuron are essential for the fine tuning of serotonergic neurotransmission. Interest in the mechanism of environmental factor-, disease-, and therapy-induced modification of 5-HT transporter (5-HTT) function and its impact on early brain development, event-related synaptic plasticity, and neurodegeneration is widespread and intensifying. We have recently characterized the human and murine 5-HTT genes and performed functional analyses of their 5'-flanking regulatory regions. A tandemly repeated sequence associated with the transcriptional apparatus of the human 5-HTT gene displays a complex secondary structure, represses promoter activity in nonserotonergic neuronal cells, and contains positive regulatory components. We now report a novel polymorphism of this repetitive element and provide evidence for allele-dependent differential 5-HTT promoter activity. Allelic variation in 5-HTT-related functions may play a role in the expression and modulation of complex traits and behavior.

Alleles↗
PubMed1996

A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders.

The serotonin transporter (5-HTT) is a candidate locus for aetiological involvement in affective disorders. Biochemical studies in suicides and depressed patients suggest that 5-HT uptake function is frequently reduced in affective illness. Furthermore, 5-HTT is targeted by widely used antidepressant drugs such as fluoxetine. We have performed an association study of a short variant of the 5-HTT-linked polymorphic region (5-HTTLPR), which restricts transcriptional activity of the 5-HTT promoter leading to low functional expression of the 5-HTT, in 454 patients with bipolar or unipolar affective disorder and 570 controls, derived from three European Centres (London, Milan and Würzburg). In all three centres, the frequency of the low activity allele was higher in patients than in controls (50% vs 45% in London, 45% vs 43% in Milan, 47% vs 40% in Würzburg). Although these differences were not individually significant, a stratified analysis of all three samples gave a significant overall odds ratio of 1.23 (95% confidence interval 1.02-1.49, P = 0.03). The excess of the homozygous low-activity genotype among the patients was even greater (odds ratio 1.53, 95% confidence interval 1.04-2.23, P = 0.02), suggesting partial recessively of the low-activity allele. Given the functional role of 5-HTT, our findings suggest that 5-HTTLPR-dependent variation in functional 5-HTT expression is a potential genetic susceptibility factor for affective disorders. If this finding is replicated, further work on genetic variants with low 5-HTT activity may facilitate the differential diagnosis of affective disorders, the assessment of suicidal behaviour, and the prediction of good clinical response to antidepressants.

Alleles↗
PubMed1995

Functional promoter and polyadenylation site mapping of the human serotonin (5-HT) transporter gene.

We have isolated and characterized the 5'-flanking region and the proximal polyadenylation site of the human 5-HT transporter gene. The major gene transcript is 2,793 bp in length and it contains 208 bp of 5'-untranslated region (5'-UTR) and 694 bases of 3'-UTR. While only a single mRNA species occurs in rats and mice, the most proximal signal for polyadenylation in the human gene appears to be highly degenerate in comparison to the rat and murine motif. This polyadenylation signal-like motif may lead to alternate usage of additional polyadenylation sites resulting in multiple mRNA species in humans. A TATA-like motif and several potential binding sites for transcription factors including AP1, AP2, SP1, and a cAMP response element (CRE)-like motif are present in the 5'-flanking region. A approximately 1.7 kb fragment beginning 217 bp downstream from the transcription start site, which had been ligated into a luciferase reporter vector and transiently expressed in JAR human placental choriocarcinoma cells, displayed both constitutive and forskolin/cholera toxin-induced promoter activity. Functional promoter mapping revealed that there are negative attenuating elements between bp -1,428 and -1,185 and positive elements between bp -1,184 and -78 from the transcription initiation site. Studies with deletional mutants also indicated that core promoter sequences are contained within 78 bp of the transcription start site and that regulation of cAMP-inducible promoter activity depends on multiple cis-acting elements including two AP1 binding sites and a single CRE-like element located at bp -99. Our findings suggest that (1) the 5-HT transporter gene promoter is active in human JAR cells, but inactive in 5-HT transporter-deficient human SK-N-SH neuroblastoma and HeLa cells, (2) the information contained within 1.4 kb of 5'-flanking sequence is sufficient to confer its cell-specific expression, (3) the promoter responds to cAMP induction, and (4) the expression of the 5-HT transporter gene is regulated by a combination of positive and negative cis-acting elements operating through a basal promoter unit defined by a TATA-like motif.

Amino Acid Sequence↗