Disease relevance of Slc6a4

• Exposure to CPF on GD9-12 elicited initial suppression, immediately followed by rebound elevation, of 5HT1A and 5HT2 receptors as well as the 5HT transporter, all at doses below the threshold for cholinergic hyperstimulation and the resultant systemic toxicity [1].
• We have constructed a bicistronic defective herpes virus (HSV-1) vector that expresses both an epitope-tagged 5HTT as well as beta-galactosidase (beta-GAL) as a marker for infected cells [2].

Psychiatry related information on Slc6a4

• A number of studies in recent years have linked polymorphisms within the serotonin transporter (5HTT) gene to affective disorders and anxiety traits [3].

High impact information on Slc6a4

• Transfection with a single 2.3-kilobase brainstem complementary DNA clone is sufficient to confer expression of a Na(+)-dependent 5HT transporter upon nonneural cells, with transport selectively and potently antagonized by 5HT uptake-specific antidepressants, including paroxetine, citalopram and fluoxetine [4].
• The 5HT transporter has significant homology to the gamma-aminobutyric acid, dopamine, and norepinephrine transporters [5].
• We have examined the effect of receptor-activated second messengers on the 5HT transporter in rat basophilic leukemia cells (RBL 2H3) [6].
• Our results suggest that the changes in transport are due to a direct modification of the 5HT transporter, possibly by phosphorylation, which appears to alter the rate at which transport occurs [6].
• Larger target sizes than expected have also been reported for ligand binding to the sodium-dependent serotonin transporter and glucose transporter [7].

Biological context of Slc6a4

• Our results indicate that CPF elicits long-lasting changes in 5HT receptors, the presynaptic 5HT transporter, and 5HT-mediated signal transduction after exposure in discrete developmental windows that range from the neural tube stage through synaptogenesis [8].
• We and others have earlier shown that severe serotonin depletion leads to a compensatory down-regulation in the expression of the serotonin transporter (5HTT) gene [9].
• Similarly, the effect of HLDL on 5HT turnover and the antagonistic interaction of EST on this HLDL-induced effect were associated with changes in 3H-IMI binding sites that label the 5HT transporter in serotonergic presynaptic terminals [10].
• IC50 values for binding these compounds to rat brain monoamine transporters were assessed using [3H]WIN 35,428 (striatal membranes, dopamine transporters, DAT), [3H]nisoxetine (frontal cortex membranes, norepinephrine transporters, NET) and [3H]paroxetine (brain stem membranes, 5HT transporters, 5HTT) [11].

Anatomical context of Slc6a4

• The human 5HTT mRNA is alternatively spliced, and the splice variants are equally expressed in the human placental cell line and dorsal raphe [3].
• In addition, since serotonin has been implicated in the mechanisms mediating the dendritic remodeling seen with other chronic stress regimens, we used quantitative autoradiography to measure binding to the serotonin transporter (5HTT) in hippocampus and dorsal and median raphe [12].
• We were also able to overexpress an epitope tagged 5HTT in serotonergic neurons in the dorsal raphe nucleus (DRN) using this approach [2].
• The vector was capable of conferring serotonin uptake activity to Vero cells in culture, indicating transfer of a functional 5HTT [2].
• [(3)H]paroxetine binding to the 5HTT was decreased in Ammon's horn in both dominants and subordinates compared to controls, while 5HTT binding remained unchanged in dentate gyrus and raphe [12].

Associations of Slc6a4 with chemical compounds

• The results concur with a single-site model of the sodium-dependent serotonin transporter with common or overlapping domains for 5-HT and 5-HT uptake inhibitors [13].
• Multiple high-dose METH injections rapidly decreased 5HT uptake without altering binding of the 5HT transporter ligand paroxetine [14].
• One of the most interesting compounds identified in the present work is a 2, 3-diaryltropane 22 in a boat conformation that is highly selective (69-fold) for the DAT over the 5HTT [15].
• Injection of the 5HTT virus into the rat brain resulted in a dense focus of specific 125I RTI-55 binding at the injection site, indicating that the virally expressed 5HTT can also bind ligand when expressed in the brain [2].
• These findings indicate that: (1) METH causes a rapid and reversible decrease in 5HT transporter activity; and (2) glutamate transporters are less susceptible than 5HT transporters to effects of reactive species or METH treatment [16].

Other interactions of Slc6a4

• S-100beta, 5HT, 5HT-transporter (5HT-T) and neurofilaments (Nf-200 and Nf-68) expressions were studied by immunohistochemistry and image analysis in striatum, hippocampus, parietal and frontal cortex [17].

References