Excitatory amino acid transporter 1 supports adult hippocampal neural stem cell self-renewal.
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PROVIDER: PRJNA896635 | ENA |
REPOSITORIES: ENA
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Project description:Within the adult mammalian dentate gyrus (DG) of the hippocampus, glutamate stimulates neural stem cell (NSC) self-renewing proliferation, providing a link between adult neurogenesis and local circuit activity. Here, we show that glutamate-induced self-renewal of adult DG NSCs requires glutamate transport via excitatory amino acid transporter 1 (EAAT1) to stimulate lipogenesis. Loss of EAAT1 prevented glutamate-induced self-renewing proliferation of NSCs in vitro and in vivo, with little role evident for canonical glutamate receptors. Transcriptomics and further pathway manipulation revealed that glutamate simulation of NSCs relied on EAAT1 transport-stimulated lipogenesis, likely secondary to intracellular Ca2+ release and glutamate metabolism. Our findings demonstrate a critical, direct role for EAAT1 in stimulating NSCs to support neurogenesis in adulthood, thereby providing insights into a non-canonical mechanism by which NSCs sense and respond their niche.
2023-06-14 | GSE217059 | GEO
Project description:Transcriptome Analysis of Human Induced Excitatory Neurons Supports a Strong Effect of Clozapine on Cholesterol Biosynthesis
| PRJNA685129 | ENA
Project description:Antipsychotics are known to modulate dopamine and other neurotransmitters which is often thought to be the mechanism underlying their therapeutic effects. Nevertheless, other less studied consequences of antipsychotics on neuronal function may contribute to their efficacy. Revealing the complete picture behind their action is of paramount importance for precision medicine and accurate drug selection. Progress in cell engineering allows the generation of induced pluripotent stem cells (iPSCs) and their differentiation to a variety of neuronal types, providing new tools to study antipsychotics. Here we use excitatory cortical neurons derived from iPSCs to explore their response to therapeutic levels of Clozapine as measured by their transcriptomic output, a proxy for neuronal homeostasis. To our surprise, but in agreement with the results of many investigators studying glial-like cells, Clozapine had a very strong effect on cholesterol metabolism. More than a quarter (12) of all annotated cholesterol genes (46) in the genome were significantly changed at FDR<0.1, all upregulated. This is a 35-fold enrichment with an adjusted p = 8 x10-11. Notably no other functional category showed evidence of enrichment. Cholesterol is a major component of the neuronal membrane and myelin but it does not cross the blood brain barrier, it is produced locally mostly by glia but also by neurons. By singling out increased expression of cholesterol metabolism genes as the main response of cortical excitatory neurons to antipsychotics, our work supports the hypothesis that cholesterol metabolism may be a contributing mechanism to the beneficial effects of Clozapine and possibly other antipsychotics.
2021-02-11 | GSE163161 | GEO
Project description:Specific autoantibodies against the NMDA-receptor (NMDAR) GluN1 subunit cause severe and debilitating NMDAR-encephalitis. Autoantibodies induce prototypic disease symptoms resembling schizophrenia, including psychosis and cognitive dysfunction. Using a mouse passive transfer model applying human monoclonal anti-GluN1-autoantibodies, we observed CA1 pyramidal neuron hypoexcitability, reduced AMPA-receptor (AMPAR) signaling, and faster synaptic inhibition resulting in disrupted excitatory-inhibitory balance. Functional alterations were supported by widespread remodeling of the hippocampal proteome, including changes in glutamatergic and GABAergic neurotransmission. At the network level, anti-GluN1-autoantibodies amplified gamma oscillations and disrupted theta-gamma coupling. A data-informed network model revealed that lower AMPAR strength and faster GABAA-receptor current kinetics chiefly account for these abnormal oscillations. As predicted by our model and evidenced experimentally, positive allosteric modulation of AMPARs alleviated aberrant gamma activity and thus reinforced the causative effects of the excitatory-inhibitory imbalance. Collectively, NMDAR-hypofunction-induced aberrant synaptic, cellular, and network dynamics provide new mechanistic insights into disease symptoms in NMDAR-encephalitis and schizophrenia.
2023-09-24 | PXD032055 | Pride
Project description:Myeloid amino acid metabolism supports solid tumor malignancy
| PRJNA518914 | ENA
Project description:The neuronal excitatory amino acid transporter 3 (EAAT3) is fairly ubiquitously expressed in the brain, though it does not necessarily maintain the same function everywhere. It is important in maintaining low local concentrations of glutamate, where its predominant post-synaptic localization can buffer nearby glutamate receptors and modulate excitatory neurotransmission and synaptic plasticity. It is also the main neuronal cysteine uptake system acting as the rate-limiting factor for the synthesis of glutathione, a potent antioxidant, in EAAT3 expressing neurons, while on GABAergic neurons, it is important in supplying glutamate as a precursor for GABA synthesis. Several diseases implicate EAAT3, and modulation of this transporter could prove a useful therapeutic approach. Regulation of EAAT3 could be targeted at several points for functional modulation, including the level of transcription, trafficking and direct pharmacological modulation, and indeed, compounds and experimental treatments have been identified that regulate EAAT3 function at different stages, which together with observations of EAAT3 regulation in patients is giving us insight into the endogenous function of this transporter, as well as the consequences of altered function. This review summarizes work done on elucidating the role and regulation of EAAT3.
| S-EPMC4969196 | biostudies-literature
Project description:Human members of the solute carrier 1 (SLC1) family of transporters take up excitatory neurotransmitters in the brain and amino acids in peripheral organs. Dysregulation of the function of SLC1 transporters is associated with neurodegenerative disorders and cancer. Here we present crystal structures of a thermostabilized human SLC1 transporter, the excitatory amino acid transporter 1 (EAAT1), with and without allosteric and competitive inhibitors bound. The structures reveal architectural features of the human transporters, such as intra- and extracellular domains that have potential roles in transport function, regulation by lipids and post-translational modifications. The coordination of the allosteric inhibitor in the structures and the change in the transporter dynamics measured by hydrogen-deuterium exchange mass spectrometry reveal a mechanism of inhibition, in which the transporter is locked in the outward-facing states of the transport cycle. Our results provide insights into the molecular mechanisms underlying the function and pharmacology of human SLC1 transporters.
| S-EPMC5410168 | biostudies-literature
Project description:The eukaryotic endocytic pathway regulates protein levels available at the plasma membrane by recycling them into specific endosomal compartments. ARFGAP1 is a component of the coat protein I (COPI) complex but it also plays a role in promoting adapter protein-2 (AP-2) mediated endocytosis. The excitatory amino acid transporter-3 (EAAT3) mediates the reuptake of glutamate from the synaptic cleft to achieve rapid termination of synaptic transmission at glutamatergic synapses. In this study, we identified two interacting proteins of EAAT3 by mass spectrometry (MS) ARFGAP1 and ARF6. We explored the role of ARFGAP1 and ARF6 in the endocytosis of EAAT3. Our data revealed that ARFGAP1 plays a role in the recycling of EAAT3, by utilizing its GTPase activating protein (GAP) activity and ARF6 acting as the substrate. ARFGAP1 promotes cargo sorting of EAAT3 via a single phenylalanine residue (F508) located at the C-terminus of the transporter. ARFGAP1-promoted AP-2 dependent endocytosis is abolished upon neutralizing F508. We utilized a heterologous expression system to identify an additional motif in the C-terminus of EAAT3 that regulates its endocytosis. Impairment in endocytosis did not affect somatodendritic targeting in cultured hippocampal neurons. Our findings support a model where endocytosis of EAAT3 is a multifactorial event regulated by ARFGAP1, occurring via the C-terminus of the transporter, and is the first study to examine the role of ARFGAP1 in the endocytosis of a transport protein.
| S-EPMC8141794 | biostudies-literature
Project description:Although a glutamate-gated chloride conductance with the properties of a sodium-dependent glutamate transporter has been described in vertebrate retinal photoreceptors and bipolar cells, the molecular species underlying this conductance has not yet been identified. We now report the cloning and functional characterization of a human excitatory amino acid transporter, EAAT5, expressed primarily in retina. Although EAAT5 shares the structural homologies of the EAAT gene family, one novel feature of the EAAT5 sequence is a carboxy-terminal motif identified previously in N-methyl-D-aspartate receptors and potassium channels and shown to confer interactions with a family of synaptic proteins that promote ion channel clustering. Functional properties of EAAT5 were examined in the Xenopus oocyte expression system by measuring radiolabeled glutamate flux and two-electrode voltage clamp recording. EAAT5-mediated L-glutamate uptake is sodium- and voltage-dependent and chloride-independent. Transporter currents elicited by glutamate are also sodium- and voltage-dependent, but ion substitution experiments suggest that this current is largely carried by chloride ions. These properties of EAAT5 are similar to the glutamate-elicited chloride conductances previously described in retinal neurons, suggesting that the EAAT5-associated chloride conductance may participate in visual processing.
| S-EPMC20584 | biostudies-literature
Project description:Glucagon supports glucose homeostasis by stimulating hepatic gluconeogenesis, in part by promoting the uptake and conversion of amino acids into gluconeogenic precursors. Genetic disruption or pharmacologic inhibition of glucagon signaling results in elevated plasma amino acids, and compensatory glucagon hypersecretion involving expansion of pancreatic α-cell mass. Regulation of pancreatic α- and β-cell growth has drawn a lot of attention because of potential therapeutic implications. Recent findings indicate that hyperaminoacidemia triggers pancreatic α-cell proliferation via an mTOR-dependent pathway. We confirm and extend these findings by demonstrating that glucagon pathway blockade selectively increases expression of the sodium-coupled neutral amino acid transporter Slc38a5 in a subset of highly proliferative α-cells, and that Slc38a5 is critical for the pancreatic response to glucagon pathway blockade; most notably, mice deficient in Slc38a5 exhibit markedly decreased α-cell hyperplasia to glucagon pathway blockade-induced hyperaminoacidemia. These results show that Slc38a5 is a key component of the feedback circuit between glucagon receptor signaling in the liver and amino acid-dependent regulation of pancreatic α-cell mass in mice.
2017-05-01 | GSE89636 | GEO