Unifying concept of serotonin transporter-associated currents.
Ontology highlight
ABSTRACT:
SUBMITTER: Schicker K
PROVIDER: S-EPMC3249096 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Serotonin (5-HT) transporter (SERT) substrates like fenfluramine and 3,4-methylenedioxymethamphetamine cause long-term depletion of brain 5-HT, while certain other substrates do not. The 5-HT deficits produced by SERT substrates are dependent upon transporter proteins, but the exact mechanisms responsible are unclear. Here, we compared the pharmacology of several SERT substrates: fenfluramine, d-fenfluramine, 1-(m-chlorophenyl)piperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperainze (TFMPP), to establish relationships between acute drug mechanisms and the propensity for long-term 5-HT depletions. In vivo microdialysis was carried out in rat nucleus accumbens to examine acute 5-HT release and long-term depletion in the same subjects. In vitro assays were performed to measure efflux of [(3)H]5-HT in rat brain synaptosomes and transporter-mediated ionic currents in SERT-expressing Xenopus oocytes. When administered repeatedly to rats (6 mg/kg, i.p., four doses), all drugs produce large sustained elevations in extracellular 5-HT (>5-fold) with minimal effects on dopamine. Importantly, 2 weeks after dosing, only rats exposed to fenfluramine and d-fenfluramine display depletion of brain 5-HT. All test drugs evoke fluoxetine-sensitive efflux of [(3)H]5-HT from synaptosomes, but d-fenfluramine and its bioactive metabolite d-norfenfluramine induce significantly greater SERT-mediated currents than phenylpiperazines. Our data confirm that drug-induced 5-HT release probably does not mediate 5-HT depletion. However, the magnitude of transporter-mediated inward current may be a critical factor in the cascade of events leading to 5-HT deficits. This hypothesis warrants further study, especially given the growing popularity of designer drugs that target SERT.
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Project description:Rare, functional, non-synonymous variants in the human serotonin (5-hydroxytryptamine, 5-HT) transporter (hSERT) gene (SLC6A4) have been identified in both autism and obsessive-compulsive disorder (OCD). Within autism, rare hSERT coding variants associate with rigid-compulsive traits, suggesting both phenotypic overlap with OCD and a shared relationship with disrupted 5-HT signalling. Here, we document functional perturbations of three of these variants: Ile425Leu; Phe465Leu; and Leu550Val. In transiently transfected HeLa cells, the three variants confer a gain of 5-HT transport phenotype. Specifically, enhanced SERT activity was also observed in lymphoblastoid lines derived from mutation carriers. In contrast to previously characterized Gly56Ala, where increased transport activity derives from catalytic activation, the three novel variants exhibit elevated surface density as revealed through both surface antagonist-binding and biotinylation studies. Unlike Gly56Ala, mutants Ile425Leu, Phe465Leu and Leu550Val retain a capacity for acute PKG and p38 MAPK regulation. However, both Gly56Ala and Ile425Leu demonstrate markedly reduced sensitivity to PP2A antagonists, suggesting that deficits in trafficking and catalytic modulation may derive from a common basis in perturbed phosphatase regulation. When expressed stably from the same genomic locus in CHO cells, both Gly56Ala and Ile425Leu display catalytic activation, accompanied by a striking loss of SERT protein.
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Project description:Irritable bowel syndrome is a frequent gastrointestinal disorder of unknown etiology. The serotonin transporter regulates the intensity and duration of serotonin signaling in the gut and is, therefore, an attractive candidate gene for irritable bowel syndrome. Previous studies investigating the 5-HTTLPR and Stin2 VNTR polymorphisms of the serotonin transporter have proved inconclusive. In this exploratory study we therefore expanded the search for a possible association of the serotonin transporter with irritable bowel syndrome to include not only the 5-HTTLPR and Stin2 VNTR length polymorphisms, but also the functional single nucleotide polymorphism rs25531. We genotyped 186 patients with irritable bowel syndrome and 50 healthy control subjects raging in age from 18 to 70 years. Carriers of the rare G allele of rs25531 had approximately threefold increased odds of irritable bowel syndrome compared with healthy controls (OR 3.3, 95% CI 1.1-9.6). Our findings suggest that further investigation of the possible role of the serotonin transporter in the etiology of IBS is warranted.
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Project description:BACKGROUND:The serotonin transporter (5-HTT) and the 5-HTTLPR/rs25531 polymorphisms in its gene (SLC6A4) have been associated with depression, increased stress-response, and brain structural alterations such as reduced hippocampal volumes. Recently, epigenetic processes including SLC6A4 promoter methylation were shown to be affected by stress, trauma, or maltreatment and are regarded to be involved in the etiology of affective disorders. However, neurobiological correlates of SLC6A4 promoter methylation have never been studied or compared to genotype effects by means of human neuroimaging hitherto METHODS:Healthy subjects were recruited in two independent samples (N?=?94, N?=?95) to obtain structural gray matter images processed by voxel-based morphometry (VBM8), focusing on hippocampal, amygdala, and anterior cingulate gyrus gray matter structure. SLC6A4 promoter methylation within an AluJb element and 5-HTTLPR/rs25531 genotypes were analyzed in view of a possible impact on local gray matter volume RESULTS:Strong associations of AluJb methylation and hippocampal gray matter volumes emerged within each sample separately, which in the combined sample withstood most conservative alpha-corrections for the entire brain. The amygdala, insula, and caudate nucleus showed similar associations. The 5-HTTLPR/rs25531 showed no main effect on gray matter, and the effect of methylation rates on hippocampal structure was comparable among the genotype groups CONCLUSIONS:Methylation within the AluJb appears to have strong effects on hippocampal gray matter volumes, indicating that epigenetic processes can alter brain structures crucially involved in stress-related disorders. Different ways of regulating SLC6A4 expression might involve exonization or transcription factor binding as potentially underlying mechanisms, which, however, is speculative and warrants further investigation.
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Project description:BACKGROUND: Several studies have hypothesized that genes regulating the components of the serotonin system, including serotonin transporter (5-HTTLPR) and serotonin 1 B receptor (5-HT1B), may be associated with alcoholism, but their results are contradictory because of alcoholism's heterogeneity. Therefore, we examined whether the 5-HTTLPR gene and 5-HT1B gene G861C polymorphism are susceptibility factors for a specific subtype of alcoholism, antisocial alcoholism in Han Chinese in Taiwan. METHODS: We recruited 273 Han Chinese male inmates with antisocial personality disorder (ASPD) [antisocial alcoholism (AS-ALC) group (n=120) and antisocial non-alcoholism (AS-N-ALC) group (n=153)] and 191 healthy male controls from the community. Genotyping was done using PCR-RFLP. RESULTS: There were no significant differences in the genotypic frequency of the 5-HT1B G861C polymorphism between the 3 groups. Although AS-ALC group members more frequently carried the 5-HTTLPR S/S, S/LG, and LG/LG genotypes than controls, the difference became non-significant after controlling for the covarying effects of age. However, the 5-HTTLPR S/S, S/LG, and LG/LG genotypes may have interacted with the 5-HT1B G861C C/C polymorphism and increased the risk of becoming antisocial alcoholism. CONCLUSION: Our study suggests that neither the 5-HTTLPR gene nor the 5-HT1B G861C polymorphism alone is a risk factor for antisocial alcoholism in Taiwan's Han Chinese population, but that the interaction between both genes may increase susceptibility to antisocial alcoholism.
| S-EPMC3583294 | biostudies-literature
Project description:The serotonin (5-HT) transporter (SERT) is a key determinant of the concentration of 5-HT available for synaptic signaling and is the target of the antidepressant-selective 5-HT reuptake inhibitors (SSRIs). In addition to the role of SERT in mediating the actions of antidepressant medications, multiple, rare gain of function coding variants in SERT have been identified in subjects with autism spectrum disorder (ASD). The Blakely lab has extensively characterized the structural and functional impact of one of these variants, SERT Ala56, in vitro and in vivo, revealing a constitutively-imposed, biased conformation that enhances transporter function and that perturbs transporter regulation. We hypothesize that SERT Ala56 disrupts the interactions of molecular networks that normally ensure proper transporter structure, localization and regulation, and whose elucidation may reveal new determinants of serotonergic dysfunction in ASD. Here, we pursue an unbiased proteomic analysis of changes in SERT interacting protein (SIPs) imposed by the SERT Ala56 variant, expressed in transgenic mice. Further investigation of the SIPs and associated networks nominated through our studies may provide new opportunities to detect and modulate brain networks that contribute to the underlying complexity of ASD.
2020-05-29 | PXD018695 | Pride