Disease relevance of SLC6A4

• Logistic regression analyses assessed associations of different polymorphisms for alpha(2) adrenoceptor and SLC6A4 with IBS or chronic abdominal pain phenotypes and high somatic score [1].
• The interaction between the SLC6A4 genotype, social stressors and chronic diseases with regard to the BL-38 score was evaluated by ANOVA [2].
• Striatal D2 and 5-HT1A receptors were studied in schizophrenia and 5-HT transporters (5-HTT) in depression and bulimia [3].
• OBJECTIVES: To clarify whether SERT-selective effects of MDMA at human monoamine transporters can account for the reported MDMA-induced selective toxicity of serotonin neurons in primate brain [4].
• Allelic variation in the serotonin transporter (5HTT) gene contributes to idiopathic pulmonary hypertension in children [5].

Psychiatry related information on SLC6A4

1. SLC6A4 and the Development of Aggressive Behaviors: The short variant of the serotonin transporter promoter gene has been found to positively correlate with aggressive behavior in a general sample of middle school children [6]. It has also been linked to aggressive conducts in the presence of attention deficit disorder in males [7], and with impulsive violent behavior in early onset alcoholism.
2. Other associations:

• Previous studies have yielded conflicting results as to the putative role of the functional polymorphism of the promoter region of the serotonin transporter gene (SLC6A4) in the etiology of anxiety-related traits and depressive disorders [2].
• Six previous family-based association studies of SLC6A4 in autistic disorder have been conducted, with four studies showing nominally significant transmission disequilibrium and two studies with no evidence of nominally significant transmission disequilibrium [8].
• Current studies have found associations of SLC6A4 polymorphisms with several psychiatric traits including bipolar affective disorder (BPD) in various populations; however, studies with contradictory results were also reported [9].
• Weight-restored patients with anorexia nervosa (AN) respond favorably to the selective serotonin reuptake inhibitor fluoxetine, which justifies association studies of the serotonin transporter gene (SLC6A4, alias SERT) and AN [10].
• The 5-HTTLPR polymorphism in the serotonin transporter gene (SLC6A4) may contribute to the risk of bipolar disorder, suicidal behavior, and neuroticism, but association to the lifetime risk of major depression has not been shown [11].
• In patients with mood disorders, we found significant difference in mean 5-HIAA concentration between 5-HTTLPR genotypes (p=0.03) [12].

High impact information on SLC6A4

• We screened for variants in the complete coding sequence and intron-exon junctions of two candidate genes for neuropsychiatric phenotypes: SLC6A4, encoding the serotonin transporter; and SLC18A2, encoding the vesicular monoamine transporter [13].
• Phosphorylation and sequestration of the serotonin transporter (SERT) were substantially impacted by ligand occupancy [14].
• Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region [15].
• The Silastic device, dubbed SERT (sustained ethanol release tube), holds 0.35 milliliter of 95 percent ethanol (by volume) and is implanted under the skin of the back where it releases ethanol for up to 12 hours, with no observable tissue damage [16].
• These transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET), which are expressed selectively on the corresponding neurons, are established targets of many psychostimulants, antidepressants, and neurotoxins [17].

Chemical compound and disease context of SLC6A4

• Transmission disequilibrium mapping at the serotonin transporter gene (SLC6A4) region in autistic disorder [8].
• CONCLUSIONS: The affinity of MDMA for the human SERT in transfected cells does not clarify the apparent selective toxicity of MDMA for serotonin neurons, although conceivably, its higher efficacy for stimulating 5-HT release may be a distinguishing factor [4].
• Serotonin and dopamine transporter (SERT, DAT) availabilities have prospectively been investigated using [123I]beta-CIT and single photon emission computed tomography in subjects with obsessive-compulsive disorder under treatment with the selective serotonin reuptake inhibitor citalopram [18].
• SERT and DAT availabilities under citalopram treatment in obsessive-compulsive disorder (OCD) [18].
• During exposure to hypoxia (10% O2 for 2 weeks), the animals received one of the specific 5-HTT inhibitors citalopram and fluoxetine (10 mg/kg/day), the selective 5-HT1B/1D receptor antagonist GR127935 (2 and 10 mg/kg/day), or the 5-HT2A receptor antagonist ketanserin (2 mg/kg/day) [19].

Biological context of SLC6A4

• In particular, two common alleles in a variable repeat sequence of the promoter region (SLC6A4) have been differentially associated with a display of abnormal levels of anxiety and affective illness in individuals carrying the "s" allele [20].
• Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism [20].
• There was no effect of SLC6A4 genotype upon serotonin transporter binding [21].
• To further elucidate the putative association between the two SLC6A4 gene polymorphisms and schizophrenia susceptibility, we performed a meta-analysis based on all original published association studies between schizophrenia and the 5-HTTLPR and STin2 VNTR polymorphisms published before April 2004 [22].
• Two functional polymorphisms within the serotonin transporter (SLC6A4) gene (promoter 44 bp insertion/deletion (HTTLPR) and an intron two 16 or 17 bp variable number tandem repeat (VNTR2)) have been extensively studied in psychiatric conditions but not in the cognitive functioning of normal individuals [23].

Anatomical context of SLC6A4

• OBJECTIVES: Serotonin transporter (SLC6A4) is responsible for serotonin re-uptake into presynaptic terminals, thus fine-tuning brain serotonergic neurotransmission [9].
• These results demonstrate genetically driven variation in the response of brain regions underlying human emotional behavior and suggest that differential excitability of the amygdala to emotional stimuli may contribute to the increased fear and anxiety typically associated with the short SLC6A4 allele [24].
• The site of action is the serotonin transporter (SLC6A4), which is expressed in brain and blood cells [25].
• The serotonin transporter (5-HTT) mRNA is found in all raphe nuclei and in the hypothalamic dorsomedial nucleus where the 5-HTT mRNA is dramatically reduced following immobilization stress [26].
• HeLa cells transfected with the Gly56Ala variant demonstrated elevated basal phosphorylation and, unlike hSERT, could not be further phosphorylated after 8-bromo cGMP (8BrcGMP) treatments [27].

Associations of SLC6A4 with chemical compounds

• Our most intriguing result involved three SNPs in the TPH1 gene and one SNP in the SLC6A4 gene, which show significant single-locus association when response to fluoxetine is compared to nonresponse (P=0.02-0.04) [28].
• In the present 12-week follow-up study, the combined effect of HTR1A and SLC6A4 genes in clinical outcome and response to citalopram was also evaluated [29].
• Because of an interaction between the serotonin (5-HT) and DA systems, the serotonin transporter gene (SLC6A4) has been considered as a candidate ADHD susceptibility gene [30].
• From this series, the dimethylated derivatives 13, 14a, 14b, 16, and 20 were radiolabeled with carbon-11 and their log P(7.4) was calculated as a measure of their potential brain penetrance as positron emission tomography SERT imaging agents [31].
• Neurotoxic reduction in 5-HTT protein expression seems to be limited to homozygous carriers of a long, more transcriptionally active allele of a promoter repeat polymorphism of the 5-HTT gene (SCL6A4) [32].

Physical interactions of SLC6A4

• With the exception of the hypoglossal nucleus, where 5-HT1A receptor binding increases while SERT binding remains stable, the medullary 5-HT markers analyzed in the study are essentially "in place" at birth [33].
• We also examine whether ITGB3 might interact with SLC6A4 to contribute to autism susceptibility [34].
• Using a yeast one-hybrid screen, we found the transcription factor Y box binding protein 1 (YB-1) interacts with the 5-HTT VNTR [35].
• The present data show that the SNARE protein syntaxin 1A binds the N-terminal tail of SERT, and this interaction regulates two SERT-conducting states [36].
• 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 [37].

Regulatory relationships of SLC6A4

• 12 weakly released from NET- and SERT-expressing cells with maximum effects less than one-tenth of that of MDMA and did not release from DAT cells [38].
• Furthermore, binding of [(11)C]AFM in SERT-rich regions was blocked by the cold compound AFM and the selective serotonin reuptake inhibitor citalopram but not by the selective norepinephrine reuptake inhibitor nisoxetine or the selective dopamine reuptake inhibitor GBR 12935 [39].
• There were also non-SERT neurons expressing ERbeta mRNA [40].
• Serotonin transporter (5-HTT) promoter genotype may influence the prolactin response to clomipramine [41].

Other interactions of SLC6A4

• METHOD: The authors assessed dopamine transporter genotype at the SLC6A3 3' variable number of tandem repeats (VNTR) polymorphism and serotonin transporter genotype at the SLC6A4 promotor VNTR polymorphism in 30 healthy subjects who also underwent single photon emission computed tomography with [(123)I]beta-CIT [21].
• RESULTS: Statistically significant positive associations were found for HTR2A and hSERT polymorphisms [42].
• CONCLUSIONS: The findings support the hypothesis that comorbid panic disorder identifies a genetic subtype of bipolar disorder and suggest a role for COMT and 5-HTT in vulnerability to these disorders [43].
• A multivariate analysis using a mixed-effects model and including age, sex and predominant ethnicity as covariates was applied to the analyses of 5HTT LPR and DRD4 length polymorphism data [44].
• The integrin beta3 (ITGB3) and serotonin transporter (SLC6A4) genes were both recently identified as male quantitative trait loci (QTLs) for serotonin levels and alleles of each have been associated with autism [34].

Analytical, diagnostic and therapeutic context of SLC6A4

• CONCLUSIONS: This study suggested that a particular SLC6A4 haplotype harboring functional sequence variant could play a significant role in BPD etiology in Taiwan. However, due to its modest sample size, the conclusion is not final and should be confirmed in the future studies [9].
• Linkage mapping of serotonin transporter protein gene SLC6A4 on chromosome 17 [45].
• A cDNA encoding a serotonin transporter (5-HTT) in the human dorsal raphe nucleus was isolated and sequenced using cross-species amplification of human 5-HTT partial cDNA by the polymerase chain reaction (PCR) and the RACE-PCR procedure, designed for rapid amplification of 3' and 5' cDNA ends [46].
• Biological assays revealed that some compounds having the N-3 atom substituted with aryl groups possess significant affinity and selectivity for monoamine transporters, and in particular, compound 5d displayed an IC50 of 21 nM toward DAT, and a good selectivity toward SERT (IC50=1042 nM) [47].
• The L-allelic variant of the 5-HTT gene promoter, which is associated with 5-HTT overexpression, was present homozygously in 14 of 25 (56%) lung transplantation patients with SPH but in only 27% of controls [48].

References