The Ionotropic AMPA receptor contributes to autoimmunity via altered regulatory T cell differentiation and function
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE275380 | GEO | 2025/11/24
REPOSITORIES: GEO
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Project description:The Ionotropic AMPA receptor contributes to autoimmunity via altered regulatory T cell differentiation and function
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Project description:Glutamate is a major excitatory neurotransmitter in the vertebrate brain. AMPA-type glutamate receptors mediate fast excitatory transmission. AMPA receptors assemble with transmembrane AMPA receptor regulatory protein (TARP) auxiliary subunits and function as native ion channels. However, the assembly and stoichiometry of AMPA receptor and TARP complexes remain unclear. Here, we developed a novel strategy to determine the assembly and stoichiometry of this protein complex and found that functional AMPA receptors indeed assembled as a tetramer in a dimer-of-dimers structure. Furthermore, we found that the AMPA receptor auxiliary subunit, TARP, had a variable stoichiometry (1-4 TARP units) on AMPA receptors and that 1 TARP unit was sufficient to modulate AMPA receptor activity. In neurons, TARP had fixed and minimum stoichiometry on AMPA receptors. This fundamental composition of the AMPA receptor/TARP complex is important for the elucidation of the molecular machinery that underlies synaptic transmission.
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Project description:The decrease in number of AMPA-type glutamate receptor (AMPAR) at excitatory synapses causes LTD, a cellular basis of learning and memory. The number of postsynaptic AMPARs is regulated by the balance of exocytosis and endocytosis, and enhanced endocytosis of AMPAR has been suggested to underlie the LTD expression. However, it remains unclear how endocytosis and exocytosis of AMPAR change during LTD. In this study, we addressed this question by analyzing exocytosis and endocytosis of AMPAR by imaging super-ecliptic pHlorin (SEP)-tagged AMPAR around postsynaptic structure formed directly on the glass surface in the hippocampal culture prepared from rat embryos of both sexes. Contrary to a prevailing view on the LTD expression by endocytosis enhancement, the LTD induction by NMDA application only transiently enhanced endocytosis of SEP-tagged GluA1 subunits of AMPAR, which was counteracted by simultaneous augmentation of exocytosis. As a result, soon after the start of the LTD induction (∼1 min), the surface AMPAR did not markedly decrease. Thereafter, the surface GluA1-SEP gradually decreased (2-5 min) and kept at a low level until the end of observation (>30 min). Surprisingly, this gradual and sustained decrease of surface AMPAR was accompanied not by the enhanced endocytic events of GluA1, but by the suppression of exocytosis. Together, our data highlight an unprecedented mechanism for the LTD expression by attenuation of exocytosis of AMPAR, but not by enhanced endocytosis, together with a reduction of postsynaptic AMPAR scaffolding protein PSD95.SIGNIFICANCE STATEMENT It has been generally assumed that LTD is expressed by enhancement of AMPAR endocytosis. Previous studies reported that endocytosis-related protein was involved in LTD and that significant amount of cell-surface AMPAR moved into intracellular compartments during LTD. Here, we report changes of cell-surface amount of AMPAR, and where and when individual exocytosis and endocytosis occurred during LTD. Cell-surface AMPAR gradually decreased in synchrony with suppression of exocytosis but not with enhancement of endocytosis. These results suggest that the decrease of cell-surface AMPAR amount during LTD was caused not by enhancement of endocytosis but rather by suppression of exocytosis, which revises current understanding of the expression mechanism of LTD.
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Project description:Transmembrane AMPA receptor regulatory proteins (TARPs) are claudin-like proteins that tightly regulate AMPA receptors (AMPARs) and are fundamental for excitatory neurotransmission. With cryo-electron microscopy (cryo-EM) we reconstruct the 36 kDa TARP subunit γ2 to 2.3 Å, which points to structural diversity among TARPs. Our data reveals critical motifs that distinguish TARPs from claudins and define how sequence variations within TARPs differentiate subfamilies and their regulation of AMPARs.
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Project description:Transmembrane AMPA receptor regulatory proteins (TARPs) are claudin-like proteins that tightly regulate AMPA receptors (AMPARs) and are fundamental for excitatory neurotransmission. We used cryo-electron microscopy (cryo-EM) to reconstruct the 36 kDa TARP subunit γ2 to 2.3 Å and reveal the structural diversity of TARPs. Our data reveals critical motifs that distinguish TARPs from claudins and define how sequence variations within TARPs differentiate subfamilies and their regulation of AMPARs.
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Project description:Recent data have shown that Hypermethylated in cancer 1 (HIC1) is an important contributor to iTreg cell development and function. Using affinity-purification and tandem mass spectrometry we systematically characterized the HIC-1 interactome in human iTreg cells. On the basis of these data, we have shown that HIC1 is a part of FOXP3-RUNX1-CBFβ protein complex that regulates Treg signature genes and is indispensable for the suppressive function of FOXP3+ regulatory T cells. SRM was used to validate HIC1 interactors
2023-10-16 | PXD039337 | Pride
Project description:In vitro data and transgenic mouse models suggest a role for TGF-? signaling in dendritic cells (DCs) to prevent autoimmunity primarily through maintenance of DCs in their immature and tolerogenic state characterized by low expression of MHC class II (MHCII) and costimulatory molecules and increased expression of IDO, among others. To test whether a complete lack of TGF-? signaling in DCs predisposes mice to spontaneous autoimmunity and to verify the mechanisms implicated previously in vitro, we generated conditional knockout (KO) mice with Cre-mediated DC-specific deletion of Tgfbr2 (DC-Tgfbr2 KO). DC-Tgfbr2 KO mice die before 15 wk of age with multiorgan autoimmune inflammation and spontaneous activation of T and B cells. Interestingly, there were no significant differences in the expression of MHCII, costimulatory molecules, or IDO in secondary lymphoid organ DCs, although Tgfbr2-deficient DCs were more proinflammatory in vitro and in vivo. DC-Tgfbr2 KO showed attenuated Foxp3 expression in regulatory T cells (Tregs) and abnormal expansion of CD25(-)Foxp3(+) Tregs in vivo. Tgfbr2-deficient DCs secreted elevated levels of IFN-? and were not capable of directing Ag-specific Treg conversion unless in the presence of anti-IFN-? blocking Ab. Adoptive transfer of induced Tregs into DC-Tgfbr2 KO mice partially rescued the phenotype. Therefore, in vivo, TGF-? signaling in DCs is critical in the control of autoimmunity through both Treg-dependent and -independent mechanisms, but it does not affect MHCII and costimulatory molecule expression.
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Project description:Chronic stress is a key risk factor for a variety of diseases, but the determinants of individual stress susceptibility are still unclear. Using a recently developed paradigm for chronic social stress in mice we identified animals that were resistant or susceptible to the persistent effects of chronic stress exposure. Gene expression analysis in laser-microdissected hippocampal subfields of both groups revealed differentially regulated AMPA receptor subunits, which might affect the susceptibility of an individual to chronic social stress. To test this hypothesis, animals were treated with the AMPA receptor potentiator LY451646 or vehicle during the last 4 weeks of chronic stress exposure. Enhanced AMPA receptor function in chronically stressed animals ameliorated the lasting effects of the chronic stress exposure on physiological, neuroendocrine and behavioural parameters. Our data suggest that differences in AMPA receptor function may underlie individual stress susceptibility and support AMPA receptor potentiators as potential medication in stress-related diseases. Keywords: phenotype, chronic stress, AMPA We have subjected 120 individuals to the chronic social stress procedure, which was recently shown to result in robust effects on neuroendocrine and behavioural parameters (Sterlemann V, 2008). Following the stress procedure all animals were single housed for 7 days. Corticosterone secretion was significantly increased in the chronic stress group compared to controls after one week of single housing. Within the chronic stress group we observed a large variation, where some individuals had recovered from the stress procedure, while others still showed a largely increased corticosterone secretion. After 4 more weeks of single housing, the difference in basal corticosterone secretion between the animals susceptible to chronic stress and unsusceptible or control subjects was still evident. From the group extremes in the chronically stressed animals we selected the 6 most-affected and the 6 most resistant individuals. To investigate the mechanisms underlying the observed differences in individual stress susceptibility between these mice we laser dissected the CA1 and the dentate gyrus region of the hippocampus in the selected mice and performed a gene expression profiling analysis. Pooled amplified RNA samples were then hybridised on Illumina mouse BeadChips (N=4 per group) and detected in the Illumina BeadArray Reader (Illumina, Inc., San Diego, CA).
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