Flotillin‐1 interacts with the serotonin transporter and modulates chronic corticosterone response

Reisinger, Sonali N.; Kong, Eryan; Molz, Barbara; Humberg, Thomas; Sideromenos, Spyridon; Cicvaric, Ana; Steinkellner, Thomas; Yang, Jae-Won; Cabatic, Maureen; Monje, Francisco J.; Sitte, Harald H.; Nichols, Benjamin J.; Pollak, Daniela D.

doi:10.1111/gbb.12482

Cited by 23 publications

(37 citation statements)

References 61 publications

(103 reference statements)

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“…Interestingly, Cremona et al [56] showed that Flotillin-1 played an important role in the internalization of dopamine transporter (DAT) and the glial glutamate transporter EAAT2, members of two different neurotransmitter transporters families. In addition to dopamine transporter and the glial glutamate transporter, a recent study of Reisinger et al revealed that Flotillin-1 modulates serotonergic neurotransmission through interacting with the serotonin transporter [58]. Considering the important role of serotonin transporter, dopamine transporter and glutamate transporter in MDD [59][60][61][62][63], it is possible that FLOT1 may be involved in MDD through modulating the internalization of dopamine transporter and the glial glutamate transporter EAAT2.…”

Section: Discussionmentioning

confidence: 99%

Integration of GWAS and brain eQTL identifies FLOT1 as a risk gene for major depressive disorder

Zhong

Zeng

et al. 2019

Neuropsychopharmacol.

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Major depressive disorder (MDD) is the most prevalent mental disorder that affects more than 200 million people worldwide. Recent large-scale genome-wide association studies (GWAS) have identified multiple risk variants that show robust association with MDD. Nevertheless, how the identified risk variants confer risk of MDD remains largely unknown. To identify risk variants that are associated with gene expression in human brain and to identify genes whose expression change may contribute to the susceptibility of MDD, we systematically integrated the genetic associations from a large-scale MDD GWAS (N = 480,359) and brain expression quantitative trait loci (eQTL) data (N = 494) using a Bayesian statistical framework (Sherlock). Sherlock integrative analysis showed that FLOT1 was significantly associated with MDD (P = 6.02 × 10 −6), suggesting that risk variants may contribute to MDD susceptibility through affecting FLOT1 expression. We further examined the expression level of FLOT1 in MDD cases and controls and found that FLOT1 was significantly upregulated in brains and peripheral blood of MDD cases compared with controls (European sample). Interestingly, we found that FLOT1 expression was also significantly upregulated in peripheral blood of first-episode drugnaive MDD cases compared with controls (P = 1.01 × 10 −7 , Chinese sample). Our study identified FLOT1 as a novel MDD risk gene whose expression level may play a role in MDD. In addition, our findings also suggest that risk variants may confer risk of MDD through affecting expression of FLOT1. Further functional investigation of FLOT1 may provide new insights for MDD pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Integration of GWAS and brain eQTL identifies FLOT1 as a risk gene for major depressive disorder

Zhong

Zeng

et al. 2019

Neuropsychopharmacol.

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“…A number of additional proteins may also interact with the intracellularly located termini. Of note, flotillin-1 [60,61] and the plasma membrane-associated GTPase Rit-2 [62,63] directly interact with monoamine transporters: They may also serve as functional regulators by changing the conformational ensemble of the termini, which behave like intrinsically disordered protein [64] or at the very least as highly dynamic protein parts [65]. The molecular details of the functional regulation is not well understood, because of the lack of sufficient high resolution structural knowledge, while it is well established that the intracellular termini of mammals have direct impact on the handling of the physiological substrates [36].…”

Section: Discussionmentioning

confidence: 99%

The Amino Terminus of LeuT Changes Conformation in an Environment Sensitive Manner

et al. 2019

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Neurotransmitter:sodium symporters are highly expressed in the human brain and catalyze the uptake of substrate through the plasma membrane by using the electrochemical gradient of sodium as the energy source. The bacterial homolog LeuT, a small amino acid transporter isolated from the bacteria Aquifex aeolicus, is the founding member of the family and has been crystallized in three conformations. The N-terminus is structurally well defined and strongly interacts with the transporter core in the outward-facing conformations. However, it could not be resolved in the inward-facing conformation, which indicates enhanced mobility. Here we investigate conformations and dynamics of the N-terminus, by combining molecular dynamics simulations with experimental verification using distance measurements and accessibility studies. We found strongly increased dynamics of the N-terminus, but also that helix TM1A is subject to enhanced mobility. TM1A moves towards the transporter core in the membrane environment, reaching a conformation that is closer to the structure of LeuT with wild type sequence, indicating that the mutation introduced to create the inward-facing structure might have altered the position of helix TM1A. The mobile N-terminus avoids entering the open vestibule of the inward-facing state, as accessibility studies do not show any reduction of quenching by iodide of a fluorophore attached to the N-terminus.

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“…A list of sample sizes employed in each experiment can be found in Supplementary Table 1. Sample sizes were determined according to own and other´s published results of comparable studies [34][35][36][37]. During all experiments prior to statistical analysis, animals´identities were numerically encoded, allowing the experimenter to be blinded to the genotype or experimental condition of each subject.…”

Section: Methodsmentioning

confidence: 99%

STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology

et al. 2020

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The signal transducer and activator of transcription 3 (STAT3) signalling pathway is activated through phosphorylation by Janus kinases in response to a diverse set of immunogenic and non-immunogenic triggers. Several distinct lines of evidence propose an intricate involvement of STAT3 in neural function relevant to behaviour in health and disease. However, in part due to the pleiotropic effects resulting from its DNA binding activity and the consequent regulation of expression of a variety of genes with context-dependent cellular consequences, the precise nature of STAT3 involvement in the neural mechanisms underlying psychopathology remains incompletely understood. Here, we focused on the midbrain serotonergic system, a central hub for the regulation of emotions, to examine the relevance of STAT3 signalling for emotional behaviour in mice by selectively knocking down raphe STAT3 expression using germline genetic (STAT3 KO) and viral-mediated approaches. Mice lacking serotonergic STAT3 presented with reduced negative behavioural reactivity and a blunted response to the sensitising effects of amphetamine, alongside alterations in midbrain neuronal firing activity of serotonergic neurons and transcriptional control of gene networks relevant for neuropsychiatric disorders. Viral knockdown of dorsal raphe (DR) STAT3 phenocopied the behavioural alterations of STAT3 KO mice, excluding a developmentally determined effect and suggesting that disruption of STAT3 signalling in the DR of adult mice is sufficient for the manifestation of behavioural traits relevant to psychopathology. Collectively, these results suggest DR STAT3 as a molecular gate for the control of behavioural reactivity, constituting a mechanistic link between the upstream activators of STAT3, serotonergic neurotransmission and psychopathology.

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Flotillin‐1 interacts with the serotonin transporter and modulates chronic corticosterone response

Cited by 23 publications

References 61 publications

Integration of GWAS and brain eQTL identifies FLOT1 as a risk gene for major depressive disorder

Integration of GWAS and brain eQTL identifies FLOT1 as a risk gene for major depressive disorder

The Amino Terminus of LeuT Changes Conformation in an Environment Sensitive Manner

STAT3 in the dorsal raphe gates behavioural reactivity and regulates gene networks associated with psychopathology

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