GluN3A-NMDA receptors constrain protein synthesis and memory by limiting synaptic GIT1/mTORC1 assembly
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA734306 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14701437.fastq.gz | Fastqsanger.gz | |||
| SRR14701439.fastq.gz | Fastqsanger.gz | |||
| SRR14701441.fastq.gz | Fastqsanger.gz | |||
| SRR14701442.fastq.gz | Fastqsanger.gz | |||
| SRR14701443.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 27 |
Similar Datasets
Project description:Protein synthesis has been implicated in learning and memory, but regulatory mechanisms operating at the synaptic level have not been identified yet. Here we characterize neuronal signaling complexes formed by the postsynaptic scaffold GIT1, the mTOR kinase and Raptor that couple synaptic stimuli to mTORC1-dependent protein synthesis; and identify non-conventional NMDA receptors containing GluN3A subunits as key negative regulators of GIT1’s binding to mTOR. GluN3A removal enables GIT1/mTOR complex formation, switches on mTORC1-dependent synthesis of plasticity proteins and enhances memory. The memory enhancement becomes evident with light training and can be achieved by selectively deleting GluN3A from excitatory neurons during adulthood. Notably, unlike the memory enhancement seen after global manipulations of translation, GluN3A deletion does not compromise memory flexibility or extinction. These findings identify a novel regulatory mechanism whereby GIT1/GluN3A interactions set local modes of protein synthesis and gate memory formation, offering a potentially selective target for cognitive enhancement.
2021-11-09 | GSE175920 | GEO
Project description:Membrane-associated guanylate kinases (MAGUKs) are the major family of scaffolding proteins at the postsynaptic density. The PSD-MAGUK subfamily, which includes PSD-95, PSD-93, SAP97, and SAP102, is well accepted to be primarily involved in the synaptic anchoring of numerous proteins, including N-methyl-D-aspartate receptors (NMDARs). Notably, the synaptic targeting of NMDARs depends on the binding of the PDZ ligand on the GluN2B subunit to MAGUK PDZ domains, as disruption of this interaction dramatically decreases NMDAR surface and synaptic expression. We recently reported a secondary interaction between SAP102 and GluN2B, in addition to the PDZ interaction. Here, we identify two critical residues on GluN2B responsible for the non-PDZ binding to SAP102. Strikingly, either mutation of these critical residues or knockdown of endogenous SAP102 can rescue the defective surface expression and synaptic localization of PDZ binding-deficient GluN2B. These data reveal an unexpected, nonscaffolding role for SAP102 in the synaptic clearance of GluN2B-containing NMDARs.
| S-EPMC3513525 | biostudies-literature
Project description:N-Methyl-d-Aspartate Receptors (NMDARs) are ionotropic glutamate-gated receptors. NMDARs are tetramers composed by several homologous subunits of GluN1-, GluN2-, or GluN3-type, leading to the existence in the central nervous system of a high variety of receptor subtypes with different pharmacological and signaling properties. NMDAR subunit composition is strictly regulated during development and by activity-dependent synaptic plasticity. Given the differences between GluN2 regulatory subunits of NMDAR in several functions, here we will focus on the synaptic pool of NMDARs containing the GluN2A subunit, addressing its role in both physiology and pathological synaptic plasticity as well as the contribution in these events of different types of GluN2A-interacting proteins.
| S-EPMC7073220 | biostudies-literature
Project description:N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that play crucial roles in brain development and synaptic plasticity. They are also therapeutic targets of interest since their dysfunction is associated with multiple neurological and psychiatric disorders. In vivo, NMDARs exist as multiple subtypes that differ in their subunit composition, anatomical distribution, functional properties, as well as signaling capacities. While much is known about diheteromeric NMDARs composed of two GluN1 subunits and two identical GluN2 (or GluN3) subunits, the majority of native NMDARs are triheteromers containing two GluN1 and two different GluN2 (or a combination of GluN2 and GluN3). Knowledge about triheteromeric NMDARs has recently boomed, with the first decoding of their atomic structure and the development of a new methodology allowing selective expression of recombinant triheteromers at the cell-surface without confounding co-expression of diheteromers. Here we review these progresses and highlight the unique attributes of triheteromers. Particular emphasis is put on GluN1/GluN2A/GluN2B triheteromers, presumably the most abundant NMDARs in the adult forebrain and critical actors of synaptic plasticity. Better understanding triheteromeric NMDAR structure and function is of major interest for brain physiology and drug discovery.
| S-EPMC5905667 | biostudies-literature
Project description:The N-methyl-d-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.
2024-05-14 | GSE245727 | GEO
Project description:The N-methyl-d-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.
2024-05-14 | GSE244607 | GEO
Project description:The N-methyl-D-aspartate (NMDA) receptor is a glutamate-activated cation channel critical to many processes in the brain. Genome-wide association studies (GWAS) suggest that glutamatergic neurotransmission and NMDA receptor-mediated synaptic plasticity is important for body weight homeostasis1. Here, we report the engineering and preclinical development of a first-in-class bimodal molecule that integrates NMDA receptor antagonism with glucagon-like peptide-1 (GLP-1) receptor agonism to effectively reverse obesity, hyperglycemia, and dyslipidemia in rodent models of metabolic disease. We demonstrate that GLP-1-directed delivery of the NMDA receptor antagonist MK-801 affects NMDA receptor-mediated synaptic plasticity in the hypothalamus. Importantly, peptide-targeting of MK-801 specifically to GLP-1 receptor-expressing brain regions circumvent adverse physiological and behavioral effects associated with MK-801 monotherapy. In sum, our approach demonstrates the feasibility of cell specific ionotropic receptor-modulation via peptide targeting and highlights the therapeutic potential of unimolecular mixed GLP-1 receptor agonism and NMDA receptor antagonism for obesity treatment.
2024-04-26 | PXD045816 | Pride
Project description:In cultured spinal neurons, NMDA receptors are absent from excitatory synapses under basal conditions, but can be made to appear at excitatory synapses following blockade of excitatory synaptic activity. The activity dependent synaptic localization of NMDA receptors is critically dependent on both the gradual, global accumulation of the NR2A and NR2B subunits and on a rapid, surface redistribution phase that is primed by the accumulation of NR2A and NR2B and inhibited by synaptic activity. Global changes in NR2A and NR2B accumulation and heterogeneous increases in synaptic NMDA receptor localization can also result from inhibitors of proteasomal processing, from manipulations of proteasomal subunit composition and from media conditioned by neurons undergoing synaptic scaling. While proteasomal processing is a mechanism shared with AMPA receptor scaling in cultured spinal neurons, diffusible factors, heterogeneity, and a rapid surface redistribution phase appear to be unique to activity dependent synaptic NMDA receptor localization.
| S-EPMC2735016 | biostudies-literature
Project description:Many excitatory synapses contain high levels of mobile zinc within glutamatergic vesicles. Although synaptic zinc and glutamate are coreleased, it is controversial whether zinc diffuses away from the release site or whether it remains bound to presynaptic membranes or proteins after its release. To study zinc transmission and quantify zinc levels, we required a high-affinity rapid zinc chelator as well as an extracellular ratiometric fluorescent zinc sensor. We demonstrate that tricine, considered a preferred chelator for studying the role of synaptic zinc, is unable to efficiently prevent zinc from binding low-nanomolar zinc-binding sites, such as the high-affinity zinc-binding site found in NMDA receptors (NMDARs). Here, we used ZX1, which has a 1 nM zinc dissociation constant and second-order rate constant for binding zinc that is 200-fold higher than those for tricine and CaEDTA. We find that synaptic zinc is phasically released during action potentials. In response to short trains of presynaptic stimulation, synaptic zinc diffuses beyond the synaptic cleft where it inhibits extrasynaptic NMDARs. During higher rates of presynaptic stimulation, released glutamate activates additional extrasynaptic NMDARs that are not reached by synaptically released zinc, but which are inhibited by ambient, tonic levels of nonsynaptic zinc. By performing a ratiometric evaluation of extracellular zinc levels in the dorsal cochlear nucleus, we determined the tonic zinc levels to be low nanomolar. These results demonstrate a physiological role for endogenous synaptic as well as tonic zinc in inhibiting extrasynaptic NMDARs and thereby fine tuning neuronal excitability and signaling.
| S-EPMC4443361 | biostudies-literature
Project description:We recentlly showed that everolimus, a mTORC1 inhibitor increases reactive oxygen species (ROS) levels, decreases the levels of NADPH and of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), and induces apoptosis of T-ALL cells.
2023-02-23 | GSE225751 | GEO