Disease relevance of Slc6a4

• These results demonstrate that osteoblastic cells express a functional serotonin system, with mechanisms for responding to and regulating uptake of 5-HT, and disruption of the 5-HTT gene may cause osteopenia [1].
• Previous studies demonstrated that the serotonin (5-hydroxytryptamine; 5-HT) transporter (5-HTT) mediates the mitogenic activity of 5-HT in pulmonary vascular SMCs and is overexpressed during hypoxia [2].
• On a preliminary screen for gross physical, neurological and behavioral functions, all measures were normal with the exception that 5-HTT -/- mice on the C57BL/6J background showed increased body weight and poor rotarod performance, and 5-HTT -/- mice on the 129S6 background showed reduced neuromuscular strength [3].
• Initial studies evaluated the dose-response and time course of 8-OH-DPAT-induced hypothermia and hormone secretion in normal CD-1 mice (the background strain of the 5-HTT knockout mice) [4].
• 5-HTT-/- mice did not develop thermal hyperalgesia, but showed bilateral mechanical allodynia after the nerve injury [5].

Psychiatry related information on Slc6a4

• Polymorphic regions consisting of a variable number of tandem repeats within intron 2 of the gene coding for the serotonin transporter protein 5-HTT have been associated with susceptibility to affective disorders [6].
• Several 3beta-(substituted phenyl)-2beta-(3-substituted isoxazol-5-yl)tropanes (3a-t) were evaluated for their ability to inhibit radioligand binding at the DAT, 5-HTT, and NET as well as in gross observation and locomotor activity in mice and in rats trained to discriminate cocaine [7].
• Food deprivation decreased MAOA mRNA in the LC (but not RN), increased TH mRNA in the LC, and did not alter NET or 5HTT mRNA levels [8].
• The present findings demonstrate abnormal behavioral phenotypes in 5-HTT null mutant mice in tests for anxiety-like and exploratory behavior, and suggest a role for the 5-HT(1A) receptor in mediating these abnormalities [9].
• 5-HTT null mutant mice provide a model to investigate the role of the 5-HTT in mood and anxiety disorders [9].

High impact information on Slc6a4

• This occurred despite potentiation of acute hypoxic pulmonary vasoconstriction in the 5-HTT(-/-) mice [2].
• These data further support a key role of 5-HTT in hypoxia-induced pulmonary vascular SMC proliferation and pulmonary hypertension [2].
• These results indicate that functional deficits in this pathway in 5-HTT(-/-) mice may be due to excessive postnatal 5-HT activity [10].
• With or without postnatal p-chlorophenylalanine treatment, 5-HTT(-/-) mice exhibited lower resting (unstimulated) lCMR(glc) than did 5-HTT(+/+) controls in the whisker-to-barrel cortex pathway and throughout the brain [10].
• FGF-2 was neuroprotective as well, because it blocked cell death induced by mutant expanded Htt in primary striatal cultures [11].

Chemical compound and disease context of Slc6a4

• Importantly, both the locomotor activity and the cocaine discrimination ED(50)values were correlated with the DAT binding but not 5-HTT and NET binding [7].

Biological context of Slc6a4

• A relatively high density of nanomolar affinity 5-HTT binding sites is present in ROS 17/2.8 and UMR 106-H5 cells [1].
• Since serotonin (5-HT) plays a role as a regulator of craniofacial morphogenesis, we explored the expression and function of 5-HT receptors and the 5-HT transporter (5-HTT) in bone [1].
• 5. Our data suggest that these polymorphic variable number of tandem repeats regions act as transcriptional regulators and have allele-dependent differential enhancer-like properties within an area of the hindbrain where the 5-HTT gene is known to be transcribed at this stage of development [6].
• Together, these data suggest that the presence of a functional 5-HTT is essential for brain 5-HT homeostasis and for 3,4-methylenedioxymethamphetamine-induced hyperactivity [12].
• Despite evidence that excess extracellular 5-HT during embryonic development, including that produced by drugs that inhibit the 5-HTT, may lead to severe craniofacial and cardiac malformations, no obvious developmental phenotype was observed in the 5-HTT-/- mice [12].

Anatomical context of Slc6a4

• The repeated administration of MDMA (10 mg/kg x 3, 3-h intervals, s.c.) significantly decreased the contents of 5-HT and its major metabolite 5-hydroxyindole acetic acid (5-HIAA) in the frontal cortex and hippocampus, and the density of the 5-HT transporter (5-HTT) in the frontal cortex, hippocampus and striatum [13].
• Primary cultures of rat osteoblasts (rOB) and a variety of clonal osteoblastic cell lines including ROS 17/2.8, UMR 106-H5 and Py1a show mRNA expression for the 5-HTT, and the 5-HT(1A), 5-HT(1D), 5-HT(2A) and 5-HT(2B) receptors by RT-PCR analysis and immunoblot [1].
• In 5-HTT (-/-) animals, cancellous bone volume (BV/TV) in the lumbar vertebrae is reduced, with a trend toward decreased trabecular thickness and trabecular number [1].
• These results indicate a role for 5-HTT in osteoclast function and suggest that commonly used antidepressive agents may affect bone mass [14].
• The functional properties of GABA(B) receptors were examined in the dorsal raphe nucleus (DRN) and the hippocampus of knock-out mice devoid of the 5-HT transporter (5-HTT-/-) or the 5-HT(1A) receptor (5-HT(1A)-/-) [15].

Associations of Slc6a4 with chemical compounds

• The serotonin transporter (5-HTT) is the molecular target of a large number of antidepressants [16].
• We now report that knockout mice without DAT and mice without 5-HTT establish cocaine-conditioned place preferences [17].
• Fluoxetine, an inhibitor of 5-HTT, reduced osteoclast differentiation but not activation [14].
• 5-HTT binding sites labeled with [125I] 3 beta-(4'-iodophenyl)tropan-2 beta-carboxylic acid methyl ester were reduced in a gene dose-dependent manner, with no demonstrable binding in 5-HTT-/- mutants [12].
• Oxytocin, but not adrenocorticotrophic hormone or corticosterone, responses to DOI were significantly greater in 5-HTT knockout mice [18].

Physical interactions of Slc6a4

• Moreover, 5-HTT binding density was significantly increased in the amygdalo-hippocampal nucleus and ventral hippocampus of the 5-HT1B KOs [19].
• Agonists at G-protein-coupled receptors in neurons of the dorsal raphe nucleus (DRN) of knock-out mice devoid of the serotonin transporter (5-HTT(-/-)) exhibit lower efficacy to inhibit cellular discharge than in wild-type counterparts [20].

Regulatory relationships of Slc6a4

• Interestingly, mPet-1 was not found in neurons transiently expressing Sert [21].
• MATERIALS AND METHODS: Using gene microarrays, we found that the serotonin transporter (5-HTT) was strongly expressed in RANKL-induced osteoclasts [14].

Other interactions of Slc6a4

• Furthermore, pretreatment and the subsequent administration of minocycline (40 mg/kg, i.p.) significantly attenuated the reduction of 5-HT and dopamine as well as the density of 5-HTT and DAT in the mouse brain by the repeated administration of MDMA [13].
• Such effects were not detected in 5-HTT-/- mice, further confirming the occurrence of marked alterations of 5-HT1A and 5-HT1B autoreceptors in these animals [22].
• We found increased expression of 5-HTT in RANKL-induced osteoclast-like cells [14].
• The density of 5-HT2C receptors was significantly increased in the amygdala and choroid plexus of 5-HTT knockout mice [18].
• Knock-out mice lacking the serotonin transporter [5-hydroxytryptamine transporter (5-HTT)] were used to assess the influence of 5-HT re-uptake on ethanol consumption [23].

Analytical, diagnostic and therapeutic context of Slc6a4

• On the tail suspension test, 5-HTT -/- mice on the 129S6 background showed a baseline antidepressant-like reduction in immobility [3].
• The results suggest that one 5-HTT function is to restrain adrenomedullary activation in response to immobilization [24].
• As shown with confocal and electron microscopy, the truncated 5-HTT does not reach the plasma membrane and is essentially retained in the endoplasmic reticulum [25].
• Here, we analyzed OCT1 and OCT3 gene expression in the brain of 5HTT knockout mice by semiquantitative competitive polymerase chain reaction and in situ hybridization [26].
• The inhibitory response of DRN neurons to intravenous injection of the 5-HT1A agonist 8-OH-DPAT was dramatically reduced in knockout 5-HTT compared with wild-type mice, especially in females [27].

References