Browse
Submit Data
Databases
API
Help

Dataset Information

33 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

CaMKIIα-driven, phosphatase-checked postsynaptic plasticity via phase separation.

ABSTRACT: Ca²⁺/calmodulin-dependent kinase IIα (CaMKIIα) is essential for synaptic plasticity and learning by decoding synaptic Ca²⁺ oscillations. Despite decades of extensive research, new mechanisms underlying CaMKIIα's function in synapses are still being discovered. Here, we discover that Shank3 is a specific binding partner for autoinhibited CaMKIIα. We demonstrate that Shank3 and GluN2B, via combined actions of Ca²⁺ and phosphatases, reciprocally bind to CaMKIIα. Under basal condition, CaMKIIα is recruited to the Shank3 subcompartment of postsynaptic density (PSD) via phase separation. Rise of Ca²⁺ concentration induces GluN2B-mediated recruitment of active CaMKIIα and formation of the CaMKIIα/GluN2B/PSD-95 condensates, which are autonomously dispersed upon Ca²⁺ removal. Protein phosphatases control the Ca²⁺-dependent shuttling of CaMKIIα between the two PSD subcompartments and PSD condensate formation. Activation of CaMKIIα further enlarges the PSD assembly and induces structural LTP. Thus, Ca²⁺-induced and phosphatase-checked shuttling of CaMKIIα between distinct PSD nano-domains can regulate phase separation-mediated PSD assembly and synaptic plasticity.

SUBMITTER: Cai Q

PROVIDER: S-EPMC7852677 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Gephyrin-mediated formation of inhibitory postsynaptic density sheet via phase separation.

Project description:Inhibitory synapses are also known as symmetric synapses due to their lack of prominent postsynaptic densities (PSDs) under a conventional electron microscope (EM). Recent cryo-EM tomography studies indicated that inhibitory synapses also contain PSDs, albeit with a rather thin sheet-like structure. It is not known how such inhibitory PSD (iPSD) sheet might form. Here, we demonstrate that the key inhibitory synapse scaffold protein gephyrin, when in complex with either glycine or GABAA receptors, spontaneously forms highly condensed molecular assemblies via phase separation both in solution and on supported membrane bilayers. Multivalent and specific interactions between the dimeric E-domain of gephyrin and the glycine/GABAA receptor multimer are essential for the iPSD condensate formation. Gephyrin alone does not form condensates. The linker between the G- and E-domains of gephyrin inhibits the iPSD condensate formation via autoinhibition. Phosphorylation of specific residues in the linker or binding of target proteins such as dynein light chain to the linker domain regulates gephyrin-mediated glycine/GABAA receptor clustering. Thus, analogous to excitatory PSDs, iPSDs are also formed by phase separation-mediated condensation of scaffold protein/neurotransmitter receptor complexes.

| S-EPMC8027005 | biostudies-literature

FAM81A is a postsynaptic protein that regulates the condensation of postsynaptic proteins via liquid-liquid phase separation.

Project description:Proteome analyses of the postsynaptic density (PSD), a proteinaceous specialization beneath the postsynaptic membrane of excitatory synapses, have identified several thousands of proteins. While proteins with predictable functions have been well studied, functionally uncharacterized proteins are mostly overlooked. In this study, we conducted a comprehensive meta-analysis of 35 PSD proteome datasets, encompassing a total of 5,869 proteins. Employing a ranking methodology, we identified 97 proteins that remain inadequately characterized. From this selection, we focused our detailed analysis on the highest-ranked protein, FAM81A. FAM81A interacts with PSD proteins, including PSD-95, SynGAP, and NMDA receptors, and promotes liquid-liquid phase separation of those proteins in cultured cells or in vitro. Down-regulation of FAM81A in cultured neurons causes a decrease in the size of PSD-95 puncta and the frequency of neuronal firing. Our findings suggest that FAM81A plays a crucial role in facilitating the interaction and assembly of proteins within the PSD, and its presence is important for maintaining normal synaptic function. Additionally, our methodology underscores the necessity for further characterization of numerous synaptic proteins that still lack comprehensive understanding.

| S-EPMC10919877 | biostudies-literature

Anchoring high concentrations of SynGAP at postsynaptic densities via liquid-liquid phase separation.

Project description:SynGAP, encoded by SYNGAP1, is a Ras/Rap GTPase activator specifically expressed in the nervous systems. SynGAP is one of the most abundant proteins in the postsynaptic densities (PSDs) of excitatory synapses and acts as a critical synaptic activity brake by tuning down synaptic GTPase activities. Mutations of SYNGAP1 have been frequently linked to brain disorders including intellectual disability, autisms, and seizure. SynGAP has been shown to undergo fast dispersions from synapses in response to stimulations, a strategy that neurons use to control the specific activities of the enzyme within the tiny, semi-open compartments in dendritic spines. However, the mechanism governing the activity-dependent synaptic localization modulations of SynGAP is poorly understood. It has been shown recently that SynGAP α1, via specifically binding to PSD-95, can undergo liquid-liquid phase separation forming membraneless, condensed protein-rich sub-compartments. This phase transition-mediated, PSD-95-dependent synaptic enrichment of SynGAP α1 not only suggests a dynamic anchoring mechanism of the protein within the PSD, but also implies a new model for the PSD formation in living neurons.

| S-EPMC6548289 | biostudies-literature

Inhibitory postsynaptic density from the lens of phase separation.

Project description:To faithfully transmit and decode signals released from presynaptic termini, postsynaptic compartments of neuronal synapses deploy hundreds of various proteins. In addition to distinct sets of proteins, excitatory and inhibitory postsynaptic apparatuses display very different organization features and regulatory properties. Decades of extensive studies have generated a wealth of knowledge on the molecular composition, assembly architecture and activity-dependent regulatory mechanisms of excitatory postsynaptic compartments. In comparison, our understanding of the inhibitory postsynaptic apparatus trails behind. Recent studies have demonstrated that phase separation is a new paradigm underlying the formation and plasticity of both excitatory and inhibitory postsynaptic molecular assemblies. In this review, we discuss molecular composition, organizational and regulatory features of inhibitory postsynaptic densities through the lens of the phase separation concept and in comparison with the excitatory postsynaptic densities.

| S-EPMC10913824 | biostudies-literature

Phase changes in neuronal postsynaptic spiking due to short term plasticity.

Project description:In the brain, the postsynaptic response of a neuron to time-varying inputs is determined by the interaction of presynaptic spike times with the short-term dynamics of each synapse. For a neuron driven by stochastic synapses, synaptic depression results in a quite different postsynaptic response to a large population input depending on how correlated in time the spikes across individual synapses are. Here we show using both simulations and mathematical analysis that not only the rate but the phase of the postsynaptic response to a rhythmic population input varies as a function of synaptic dynamics and synaptic configuration. Resultant phase leads may compensate for transmission delays and be predictive of rhythmic changes. This could be particularly important for sensory processing and motor rhythm generation in the nervous system.

| S-EPMC5627952 | biostudies-literature

Phase Transition in Postsynaptic Densities Underlies Formation of Synaptic Complexes and Synaptic Plasticity.

Project description:Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95. Binding of SynGAP to PSD-95 induces phase separation of the complex, forming highly concentrated liquid-like droplets reminiscent of the PSD. The multivalent nature of the SynGAP/PSD-95 complex is critical for the phase separation to occur and for proper activity-dependent SynGAP dispersions from the PSD. In addition to revealing a dynamic anchoring mechanism of SynGAP at the PSD, our results also suggest a model for phase-transition-mediated formation of PSD.

| S-EPMC5564291 | biostudies-literature

PLPP/CIN regulates bidirectional synaptic plasticity via GluN2A interaction with postsynaptic proteins.

Project description:Dendritic spines are dynamic structures whose efficacies and morphologies are modulated by activity-dependent synaptic plasticity. The actin cytoskeleton plays an important role in stabilization and structural modification of spines. However, the regulatory mechanism by which it alters the plasticity threshold remains elusive. Here, we demonstrate the role of pyridoxal-5'-phosphate phosphatase/chronophin (PLPP/CIN), one of the cofilin-mediated F-actin regulators, in modulating synaptic plasticity in vivo. PLPP/CIN transgenic (Tg) mice had immature spines with small heads, while PLPP/CIN knockout (KO) mice had gigantic spines. Furthermore, PLPP/CIN Tg mice exhibited enhanced synaptic plasticity, but KO mice showed abnormal synaptic plasticity. The PLPP/CIN-induced alterations in synaptic plasticity were consistent with the acquisition and the recall capacity of spatial learning. PLPP/CIN also enhanced N-methyl-D-aspartate receptor (GluN) functionality by regulating the coupling of GluN2A with interacting proteins, particularly postsynaptic density-95 (PSD95). Therefore, these results suggest that PLPP/CIN may be an important factor for regulating the plasticity threshold.

| S-EPMC4876383 | biostudies-literature

SK Channel Modulates Synaptic Plasticity by Tuning CaMKIIα/β Dynamics.

Project description:N-Methyl-D-Aspartate Receptor 1 (NMDAR)-linked Ca++ current represents a significant percentage of post-synaptic transient that modulates synaptic strength and is pertinent to dendritic spine plasticity. In the hippocampus, Ca++ transient produced by glutamatergic ionotropic neurotransmission facilitates Ca++-Calmodulin-dependent kinase 2 (CaMKII) Thr286 phosphorylation and promote long-term potentiation (LTP) expression. At CA1 post-synaptic densities, Ca++ transients equally activate small conductance (SK2) channel which regulates excitability by suppressing Ca++ movement. Here, we demonstrate that upstream attenuation of GluN1 function in the hippocampus led to a decrease in Thr286 CaMKIIα phosphorylation, and increased SK2 expression. Consistent with the loss of GluN1 function, potentiation of SK channel in wild type hippocampus reduced CaMKIIα expression and abrogate synaptic localization of T286 pCaMKIIα. Our results demonstrate that positive modulation of SK channel at hippocampal synapses likely refine GluN1-linked plasticity by tuning dendritic localization of CaMKIIα.

| S-EPMC6834780 | biostudies-literature

Liquid-liquid phase separation driven compartmentalization of reactive nucleoplasm.

Project description:The nucleus of eukaryotic cells harbors active and out of equilibrium environments conducive to diverse gene regulatory processes. On a molecular scale, gene regulatory processes take place within hierarchically compartmentalized sub-nuclear bodies. While the impact of nuclear structure on gene regulation is widely appreciated, it has remained much less clear whether and how gene regulation is impacting nuclear order itself. Recently, the liquid-liquid phase separation emerged as a fundamental mechanism driving the formation of biomolecular condensates, including membrane-less organelles, chromatin territories, and transcriptional domains. The transience and environmental sensitivity of biomolecular condensation are strongly suggestive of kinetic gene-regulatory control of phase separation. To better understand kinetic aspects controlling biomolecular phase-separation, we have constructed a minimalist model of the reactive nucleoplasm. The model is based on the Cahn-Hilliard formulation of ternary protein-RNA-nucleoplasm components coupled to non-equilibrium and spatially dependent gene expression. We find a broad range of kinetic regimes through an extensive set of simulations where the interplay of phase separation and reactive timescales can generate heterogeneous multi-modal gene expression patterns. Furthermore, the significance of this finding is that heterogeneity of gene expression is linked directly with the heterogeneity of length-scales in phase-separated condensates.

| S-EPMC8201646 | biostudies-literature

Mechanically-driven phase separation in a growing bacterial colony.

Project description:Secretion of extracellular polymeric substances (EPSs) by growing bacteria is an integral part of forming biofilm-like structures. In such dense systems, mechanical interactions among the structural components can be expected to significantly contribute to morphological properties. Here, we use a particle-based modeling approach to study the self-organization of nonmotile rod-shaped bacterial cells growing on a solid substrate in the presence of self-produced EPSs. In our simulation, all of the components interact mechanically via repulsive forces, occurring as the bacterial cells grow and divide (via consuming diffusing nutrient) and produce EPSs. Based on our simulation, we show that mechanical interactions control the collective behavior of the system. In particular, we find that the presence of nonadsorbing EPSs can lead to spontaneous aggregation of bacterial cells by a depletion attraction and thereby generates phase separated patterns in the nonequilibrium growing colony. Both repulsive interactions between cell and EPSs and the overall concentration of EPSs are important factors in the self-organization in a nonequilibrium growing colony. Furthermore, we investigate the interplay of mechanics with the nutrient diffusion and consumption by bacterial cells and observe that suppression of branch formation occurs due to EPSs compared with the case where no EPS is produced.

| S-EPMC4418877 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data