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Impact of the dopamine transporter knockdown in human colorectal cancer cells

ABSTRACT: Impact of the dopamine transporter knockdown in human colorectal cancer cells

PROVIDER: PRJNA939706 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23647783.fastq.gz	Fastqsanger.gz
	SRR23647784.fastq.gz	Fastqsanger.gz
	SRR23647785.fastq.gz	Fastqsanger.gz
	SRR23647786.fastq.gz	Fastqsanger.gz
	SRR23647787.fastq.gz	Fastqsanger.gz

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The dopamine transporter antiports potassium to increase the uptake of dopamine

Project description:The dopamine transporter facilitates dopamine reuptake from the extracellular space to terminate neurotransmission. The transporter belongs to the neurotransmitter:sodium symporter family, which includes transporters for serotonin, norepinephrine, and GABA that utilize the Na+ gradient to drive the uptake of substrate. Decades ago, it was shown that the serotonin transporter also antiports K+, but investigations of K+-coupled transport in other neurotransmitter:sodium symporters have been inconclusive. Here, we show that ligand binding to the drosophila- and human dopamine transporters are inhibited by K+, and the conformational dynamics of the drosophila dopamine transporter in K+ are divergent from the apo- and Na+-states. Furthermore, we found that K+ increased dopamine uptake by the drosophila dopamine transporter in liposomes, and visualized Na+ and K+ fluxes in single proteoliposomes using fluorescent ion indicators. Our results expand on the fundamentals of dopamine transport and prompt a reevaluation of the impact of K+ on other transporters in this pharmacologically important family.

2022-05-20 | PXD032663 | Pride

Impact of the dopamine transporter knockdown in human colorectal cancer cells

Project description:Here, we performed transcriptome-profiling experiments on control scramble shRNA and shSLC6A3 HCT116 cells to study the impact DAT silencing on gene networks associated with neoplastic stemness. We also treated control HCT116 cells with the DAT agonist vanoxerine (VXN) to identify commonly regulated networks between DAT knockdown and pharmacological antagonism.

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Substrate-induced conformational dynamics of the dopamine transporter

Project description:The dopamine transporter is a member of the neurotransmitter:sodium symporters (NSSs), which are responsible for termination of neurotransmission through Na+-driven reuptake of neurotransmitter from the extracellular space. Experimental evidence elucidating the coordinated conformational rearrangements related to the transport mechanism has so far been limited. Here we probe the global Na+- and dopamine-induced conformational dynamics of the wild-type Drosophila melanogaster dopamine transporter using hydrogen-deuterium exchange mass spectrometry. We identify Na+- and dopamine-induced changes in specific regions of the transporter, suggesting their involvement in protein conformational transitions. Furthermore, we detect ligand-dependent slow cooperative fluctuations of helical stretches in several domains of the transporter, which could be a molecular mechanism that assists in the transporter function. Our results provide a framework for understanding the molecular mechanism underlying the function of NSSs by revealing detailed insight into the state-dependent conformational changes associated with the alternating access model of the dopamine transporter.

2019-11-12 | PXD013841 | Pride

Microarray analysis of a Drosophila dopamine transporter mutant, fumin (fmn)

Project description:We previously found a short sleeper mutant, fmn, and identified its mutation in the dopamine transporter gene. In an attempt to discover additional sleep related genes in Drosophila, we carried out a microarray analysis comparing mRNA expression in heads of fmn and control flies and found differentially expressed genes. Next, using the pan-neuronal Gal4 driver elav-Gal4 and UAS-RNA interference (RNAi) to knockdown individual genes, we performed a functional screen. We found that knockdown of the NMDA type glutamate receptor channel gene (Nmdar1) reduced sleep.

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Dopamine transporter and synaptic vesicle sorting defects underlie auxilin-associated Parkinson’s disease

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Project description:Dopaminergic (DA) neurons are the predominant cell type in the midbrain that synthesize dopamine, a neurotransmitter implicated in various behavioural processes, including motor function, the reward pathway, and satiety. In diseases affecting these neurons, such as in Parkinson’s disease (PD), there is growing evidence that the gut-brain axis and selective vulnerability of DA neurons plays a crucial role in disease. Most investigations relating to DA neurons in the gut rely on immunoreactivity to tyrosine hydroxylase (TH) - a rate-limiting enzyme in the production of dopamine. However, the reliability of TH staining as a marker of DA neurons has been questioned in recent years. Our aim is to perform a comprehensive characterization of DA neurons in the gut using a well-accepted reporter mouse line, expressing a fluorescent protein under the dopamine transporter promoter (DAT). Our findings confirm a unique localization of DA neurons in the gut, and unveil that there are discrete subtypes of DA neurons in the gut, which we characterized using both immunofluorescence and single-cell transcriptomics. We observed distinct subtypes of DAT neurons expressing co-transmitters and modulators across both plexuses; some of them likely co-releasing acetylcholine, and a smaller population likely releasing nitric oxide; while others were positive for a slew of canonical DA markers (Vmat2, Girk2, Foxa2). Given the clear heterogeneity of DA gut neurons, further investigation is warranted to define their functional signatures and discover their inherent biological differences that predispose these cells to neurodegeneration.

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Characterizing the diversity of enteric neurons using Dopamine Transporter (DAT)-Cre reporter mice

Project description:Characterizing the diversity of enteric neurons using Dopamine Transporter (DAT)-Cre reporter mice

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