Affinage

ARC

Nucleolar protein 3 · UniProt O60936

Length
208 aa
Mass
22.6 kDa
Annotated
2026-06-09
100 papers in source corpus 29 papers cited in narrative 29 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Arc/Arg3.1 is an activity-induced immediate early gene product that couples neuronal activity to the structural and functional remodeling of synapses, acting as a multidomain hub for AMPA receptor trafficking and homeostatic plasticity (PMID:17088213, PMID:17088212). Its transcription is gated by a synaptic activity-responsive element (SARE) carrying CREB, MEF2, and SRF sites (PMID:19116276), while its protein output is further controlled translationally through convergent NMDA receptor and Gs/cAMP/PKA signaling (PMID:17981809) and by dendritic mRNA targeting that depends on actin polymerization and ERK1/2 (PMID:17715342). At the synapse, Arc drives clathrin-mediated endocytosis of GluR2/3- and GluA1-containing AMPARs through direct interaction with endophilin 2/3 and dynamin 2/3 — but not dynamin 1 — stimulating dynamin polymerization and GTPase activity, and weakening synapses during mGluR-LTD and homeostatic scaling (PMID:17088211, PMID:17088212, PMID:18614031, PMID:25783003). Arc additionally disperses AMPARs by directly antagonizing PSD-95 binding to TARPs in phase-separated postsynaptic densities, an action blocked by TARP phosphorylation so that active synapses are spared (PMID:35856091), and it is selectively targeted to inactive synapses via high-affinity binding to calmodulin-free CaMKIIβ (inverse synaptic tagging) (PMID:22579289). Beyond receptor trafficking, sustained Arc synthesis stabilizes LTP by promoting cofilin phosphorylation and F-actin expansion (PMID:17898216), and Arc mediates developmental and MEF2-driven synapse elimination (PMID:23791196, PMID:24857654). Arc also functions in the nucleus, where it associates with β-spectrin and PML bodies to suppress GluA1 transcription and engage chromatin at active enhancers, regulating broad activity-dependent gene programs (PMID:23749147, PMID:17466953, PMID:36009494). Arc is a modular, self-oligomerizing protein (PMID:25748042) that is palmitoylated for membrane insertion (PMID:29264923) and whose levels are tightly bounded by GSK3α/β phosphorylation and ubiquitin-proteasome degradation, with these turnover controls shaping mGluR-LTD threshold and cognitive flexibility (PMID:28670266, PMID:29861284). Arc further contributes to activity-dependent β-amyloid generation by trafficking APP, BACE1, and presenilin-1 through endosomes (PMID:22036569). A distinct anti-apoptotic ARC (Apoptosis Repressor with CARD domain) is ubiquitinated and degraded by MDM2 under oxidative stress (PMID:17142834); this protein is functionally unrelated to the synaptic Arc and represents a symbol collision within the corpus.

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2006 High

    Established Arc as a direct effector of AMPA receptor endocytosis, defining the core synapse-weakening machinery rather than leaving Arc as a correlative activity marker.

    Evidence Co-IP and pulldown with dynamin/endophilin 2/3, endocytosis and surface-AMPAR assays in Arc KO neurons; electrophysiology with domain-deletion and clathrin blockade

    PMID:17088211 PMID:17088212 PMID:17088213

    Open questions at the time
    • Stoichiometry and structural basis of the endophilin/dynamin complex not resolved
    • Did not address selectivity between AMPAR subunit compositions at atomic level
  2. 2007 High

    Linked Arc to LTP consolidation by showing it sustains cytoskeletal remodeling, separating Arc's role in synapse strengthening from its endocytic weakening function.

    Evidence In vivo temporal antisense knockdown in dentate gyrus with cofilin phosphorylation/F-actin readouts and jasplakinolide rescue

    PMID:17898216

    Open questions at the time
    • Direct molecular link between Arc and the cofilin/actin kinases not defined
    • How one protein both removes AMPARs and stabilizes F-actin unresolved
  3. 2007 Medium

    Began defining nuclear Arc by identifying a β-spectrin partner and PML body association, and dissected upstream translational/mRNA-targeting control.

    Evidence Co-IP and co-localization with betaSpIVSigma5 and domain analysis; pharmacological dissection of NMDA/Gs/cAMP and Rho-kinase/ERK control of Arc translation and mRNA localization

    PMID:17466953 PMID:17715342 PMID:17981809

    Open questions at the time
    • No functional consequence established for the β-spectrin interaction in 2007
    • Translational regulators acting directly on Arc mRNA not identified
  4. 2008 High

    Identified the SARE enhancer and assigned Arc-dependence specifically to mGluR-LTD, sharpening which plasticity pathways require Arc.

    Evidence Luciferase reporter dissection with CREB/MEF2/SRF site mapping; Arc knockdown blocking mGluR but not NMDAR-dependent LTD endocytosis

    PMID:18614031 PMID:19116276

    Open questions at the time
    • Combinatorial logic of CREB/MEF2/SRF at SARE not resolved
    • Mechanism distinguishing mGluR- from NMDAR-LTD endocytosis pathways unclear
  5. 2011 High

    Explained synapse-specificity of Arc action via inverse synaptic tagging and extended Arc's reach to endosomal Aβ generation and Notch signaling.

    Evidence Co-IP and live imaging with CaMKIIβ KO; Arc KO in AD transgenic mice with endosome trafficking and Aβ assays; Notch1 cleavage in Arc mutant neurons

    PMID:21315255 PMID:22036569 PMID:22579289

    Open questions at the time
    • Structural basis of calmodulin-free CaMKIIβ recognition not defined
    • Notch1 regulation mechanistically shallow (single-lab, two contexts)
  6. 2013 High

    Defined nuclear Arc as a homeostatic regulator that suppresses GluA1 transcription via PML bodies, and extended Arc to developmental synapse elimination.

    Evidence Domain mutagenesis of NLS/retention/export with PML quantification and electrophysiology in Arc KO; PC-specific knockdown with optogenetics and VDCC epistasis; MEF2/mGluR5-driven elimination with dendritic translation

    PMID:23749147 PMID:23791196 PMID:24857654

    Open questions at the time
    • How Arc mechanistically lowers GluA1 transcription at the promoter unresolved
    • Link between nuclear and synaptic Arc pools not quantified
  7. 2015 High

    Provided biochemical and biophysical groundwork by showing Arc is a modular self-oligomerizing protein that activates specific dynamin isoforms.

    Evidence Limited proteolysis/CD/DLS/AFM/EM on purified Arc; reconstituted GTPase and polymerization assays establishing dynamin 2/3 vs dynamin 1 selectivity

    PMID:25748042 PMID:25783003

    Open questions at the time
    • High-resolution full-length structure absent
    • Functional role of oligomerization in cells not directly tested
  8. 2017 High

    Established post-translational control of Arc: palmitoylation for membrane insertion and GSK3-dependent phosphorylation/ubiquitination for turnover, both tied to plasticity output.

    Evidence Palmitoylation/liposome assays with cysteine-motif mutants and MEF2 depression readout; in vitro kinase assays and degradation-resistant mutants with spine morphology; chromatin ChIP-seq and KD transcriptomics

    PMID:28670266 PMID:29264923 PMID:36009494

    Open questions at the time
    • Palmitoyl-acyltransferase responsible for Arc not identified
    • Direct GSK3 phosphosites versus ubiquitin sites not fully mapped
  9. 2018 High

    Demonstrated that proteasomal control of Arc levels sets the threshold for mGluR-LTD and cognitive flexibility, causally linking Arc turnover to behavior.

    Evidence ArcKR ubiquitination-site knockin mice with mGluR-LTD electrophysiology and reversal-learning behavior

    PMID:29861284

    Open questions at the time
    • E3 ligase(s) acting on synaptic Arc not identified
    • Circuit-level basis of reversal-learning deficit not resolved
  10. 2022 High

    Revealed a non-endocytic synapse-weakening mechanism: Arc competitively disrupts PSD-95-TARP condensates, with phospho-TARP gating protecting active synapses.

    Evidence Phase separation reconstitution with purified proteins, competitive binding, TARP phospho-mutants, and spine imaging

    PMID:35856091

    Open questions at the time
    • Relative in vivo contribution of TARP dispersal versus endocytosis unquantified
    • Structural basis of Arc-TARP competition with PSD-95 not solved
  11. 2020 Medium

    Extended Arc beyond canonical plasticity to systems-level and peripheral functions, including sleep homeostasis, dendritic-cell migration, neurogenic inflammation, drug-memory reconsolidation, and heat shock response.

    Evidence Arc KO sleep phenotyping with subcellular fractionation; DC migration with myosin II; EV-rescued vasodilation; NAc antisense in morphine CPP; HSF1 Co-IP/ChIP

    PMID:14969744 PMID:25746394 PMID:28783680 PMID:30796345 PMID:32350140 PMID:34326146

    Open questions at the time
    • Mechanistic depth for non-neuronal roles is limited and single-lab
    • Whether intercellular EV-mediated Arc transfer operates in the CNS untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved how Arc's distinct biochemical modes — endocytic adaptor, TARP-condensate disruptor, nuclear transcriptional regulator, and oligomeric scaffold — are coordinately deployed within a single neuron and how the synaptic Arc relates to the unrelated anti-apoptotic ARC (CARD) protein in the corpus.
  • No unified structural model linking Arc's domains to its multiple activities
  • Switch determining nuclear versus synaptic Arc fate unknown
  • Symbol collision with apoptotic ARC complicates corpus interpretation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3 GO:0008092 cytoskeletal protein binding 2 GO:0140110 transcription regulator activity 2 GO:0008289 lipid binding 1
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-74160 Gene expression (Transcription) 3 R-HSA-1266738 Developmental Biology 2
Partners
CAMK2BDNM2DNM3HSF1PSEN1SH3GL2SH3GL3SPTBN4
Complex memberships
PML nuclear body

Evidence

Reading pass · 29 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2006 Arc/Arg3.1 protein interacts with dynamin and specific isoforms of endophilin (endophilin 2/3) to enhance AMPA receptor endocytosis, accelerating internalization and reducing surface expression of AMPARs. Arc KO neurons exhibit markedly reduced endocytosis and increased steady-state surface AMPAR levels. Co-immunoprecipitation, pulldown assays, endocytosis assays in neurons, Arc KO analysis Neuron High 17088211
2006 Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors: high Arc levels block homeostatic increases in AMPAR function induced by chronic inactivity, and loss of Arc results in increased AMPAR function and abolishes homeostatic scaling. Arc activates a selective AMPAR endocytic pathway. Electrophysiology, Arc KO mice, Arc overexpression, AMPAR surface expression assays Neuron High 17088213
2006 Arc/Arg3.1 reduces AMPA receptor-mediated synaptic currents specifically by removing GluR2/3-containing AMPARs via an endocytosis pathway dependent on its endophilin 3 interaction domain and clathrin-coated endocytosis. Arc expression occludes NMDAR-dependent LTD. Electrophysiology, RNAi knockdown, Arc domain deletion mutants, clathrin endocytosis blockade Neuron High 17088212
2007 Sustained Arc/Arg3.1 synthesis during LTP consolidation is required for cofilin phosphorylation and stable expansion of the F-actin cytoskeleton at synaptic sites in the dentate gyrus in vivo. Antisense knockdown of Arc at 2 h post-LTP induction causes rapid and permanent reversal of LTP, dephosphorylation of cofilin, and loss of nascent F-actin. In vivo antisense oligodeoxynucleotide infusion at multiple time points, F-actin staining, cofilin phosphorylation assays, F-actin stabilizing drug (jasplakinolide) rescue The Journal of neuroscience High 17898216
2008 mGluR-LTD in hippocampal neurons requires rapid dendritic translation of Arc. mGluR activation causes long-term increases in AMPAR endocytosis rate and dendritic synthesis of Arc. Knockdown of Arc prevents mGluR-triggered AMPAR endocytosis or LTD. NMDAR-dependent LTD does not require Arc. Arc antisense oligonucleotide knockdown, AMPAR endocytosis assays, electrophysiology, Arc RNAi Neuron High 18614031
2008 The Arc/Arg3.1 promoter contains a ~100-bp synaptic activity-responsive element (SARE) located >5 kb upstream of the transcription start site that is necessary and sufficient for activity-dependent Arc transcription. SARE contains closely localized binding sites for CREB, MEF2, and SRF transcription factors. Luciferase reporter assays in cultured cortical neurons, comparative genome mapping, SARE element deletion/mutation analysis, in vivo reporter tracing Proceedings of the National Academy of Sciences of the United States of America High 19116276
2011 Activity-induced Arc preferentially targets inactive synapses via high-affinity interaction with CaMKIIβ not bound to calmodulin (inverse synaptic tagging). Arc accumulation at inactive synapses correlates with removal of surface GluA1. Loss of CaMKIIβ in vitro or in vivo eliminates Arc upregulation in silenced synapses. Co-immunoprecipitation, live imaging, immunostaining in cultured neurons and in vivo, CaMKIIβ KO analysis, surface GluA1 quantification Cell High 22579289
2011 Arc regulates an endosomal pathway that controls β-amyloid generation: Arc recruits endophilin2/3 and dynamin to early/recycling endosomes that traffic APP and BACE1. Arc physically associates with presenilin1 (PS1) to regulate γ-secretase trafficking and confer activity dependence to Aβ generation. Genetic deletion of Arc reduces Aβ load in a transgenic AD mouse model. Co-immunoprecipitation, endosome trafficking assays, Arc KO in transgenic AD mice, Aβ measurements Cell High 22036569
2011 Arc/Arg3.1 positively regulates proteolytic (signaling) activation of Notch1 in neurons in response to synaptic activity. In Arc mutant neurons, proteolytic activation of Notch1 is disrupted both in vivo and in vitro. Arc KO neurons, Notch1 cleavage assays in vivo and in vitro, immunostaining, conditional Notch1 deletion Neuron Medium 21315255
2013 Arc nuclear localization promotes activity-induced increase in promyelocytic leukemia (PML) nuclear body expression, which decreases GluA1 transcription and synaptic strength, thereby mediating homeostatic plasticity. Distinct Arc domains control nuclear localization signal, nuclear retention, and nuclear export. Arc domain mutagenesis, live fluorescence imaging, PML body quantification, GluA1 transcription assays, electrophysiology in Arc KO neurons Nature neuroscience High 23749147
2013 Arc/Arg3.1 mediates elimination of surplus climbing fiber synapses onto Purkinje cells in the developing cerebellum, acting downstream of P/Q-type voltage-dependent Ca2+ channels (VDCCs). PC-specific Arc knockdown impairs CF synapse elimination; this effect is occluded by simultaneous P/Q-type VDCC knockdown. PC-specific lentiviral Arc knockdown, channelrhodopsin-2 photostimulation, confocal imaging of CF synapse number, double knockdown epistasis Neuron High 23791196
2013 Arc/Arg3.1 is required for MEF2-induced synapse elimination, and dendritic mGluR5 activation (not somal) is necessary for MEF2-induced synapse elimination through local dendritic translation of Arc. Arc plays an acute, cell-autonomous, postsynaptic role. Compartment-specific mGluR5 activation, Arc knockdown, spine density/functional synapse counts, dendritic translation assays Cell reports Medium 24857654
2015 Recombinant human Arc is a modular protein with two major domains flanking a disordered linker, capable of reversible self-oligomerization from monomers to large soluble oligomers. The N-terminal domain is highly basic, the C-terminal domain is acidic and stabilized by ionic conditions. Binding of presenilin-1 (PS1) peptide induces a large structural change in Arc. Limited proteolysis/MS, CD spectroscopy, thermal denaturation, dynamic light scattering, AFM, EM, differential scanning fluorimetry The Biochemical journal High 25748042
2015 Arc enhances dynamin 2 polymerization and stimulates its GTPase activity under physiological conditions. Arc also increases GTPase activity of dynamin 3 but not dynamin 1. Arc forms large soluble oligomers that may scaffold dynamin assembly and activation. Enzymatic GTPase assays, turbidity assays, size exclusion chromatography, sedimentation analysis, dynamic light scattering, fluorescence correlation spectroscopy, electron microscopy with purified proteins Biochimica et biophysica acta High 25783003
2017 Arc undergoes palmitoylation in neurons at cysteines in a 94CLCRC98 motif in its N-terminal half, enabling direct insertion into membrane lipid bilayers. Arc palmitoylation mutant (three cysteines mutated) cannot support MEF2-induced synaptic depression, demonstrating that palmitoylation regulates a subset of Arc's synaptic plasticity functions. Palmitoylation assays in neurons, liposome binding assays with purified protein, site-directed mutagenesis, synaptic depression assays Biochemistry High 29264923
2017 GSK3α and GSK3β phosphorylate Arc and promote its degradation. GSK3β terminates Arc expression and limits its effect on dendritic spine morphology. Arc mutants resistant to GSK3β-mediated phosphorylation or ubiquitination produce stronger reduction of dendritic spine width than wild-type Arc. In vitro kinase assays, site-directed mutagenesis of Arc phosphorylation sites, proteasome inhibitor treatments, dendritic spine morphology analysis, GSK3 inhibitor pharmacology Frontiers in molecular neuroscience High 28670266
2018 Proteasome-dependent degradation of Arc, mediated primarily through ubiquitination at specific sites, controls the temporal dynamics of Arc expression. ArcKR knockin mice (ubiquitination sites mutated) show a reduced threshold for mGluR-LTD induction and enhanced mGluR-LTD amplitude, and display deficits in reversal learning (cognitive flexibility), without impaired spatial learning. Arc knockin mouse generation (ubiquitination site mutation), electrophysiology (mGluR-LTD), behavioral testing (reversal learning, spatial learning) Neuron High 29861284
2007 Arc protein associates with betaIV spectrin splice variant betaSpIVSigma5 in the nucleus and co-localizes with PML bodies. Arc and betaSpIVSigma5 synergistically increase PML body number. The coiled-coil domain of Arc is required for nuclear puncta localization. Co-immunoprecipitation, fluorescence microscopy, domain deletion analysis in neurons and HEK293T cells Brain research Medium 17466953
2007 Arc protein translation is controlled by convergent NMDA receptor and Gs-coupled receptor (dopamine, β-adrenergic) signaling through the cAMP/PKA pathway. Gs-coupled receptor stimulation is ineffective in raising Arc protein in the absence of NMDA receptor activity, indicating NMDA-gated calcium influx plays a permissive role. The effect is post-transcriptional (translational efficacy) with no change in Arc mRNA level. Fluorescence microscopy for Arc protein quantification, pharmacological receptor activation/blockade, mRNA level measurement, protein stability assays in cultured hippocampal neurons The Journal of biological chemistry Medium 17981809
2007 Actin polymerization (via Rho kinase signaling) and ERK1/2 phosphorylation are both required for targeting newly synthesized Arc/Arg3.1 mRNA to activated synaptic sites on dendrites following high-frequency stimulation. Local inhibition of Rho kinase or latrunculin B blocks actin polymerization and Arc mRNA localization in the same dendritic domain. In vivo local pharmacological inhibition (Rho kinase inhibitor, latrunculin B, MEK inhibitor U0126), fluorescence in situ hybridization for Arc mRNA localization The Journal of neuroscience Medium 17715342
2006 MDM2, a p53-induced E3 ubiquitin ligase, directly ubiquitinates ARC (Apoptosis Repressor with CARD domain, the anti-apoptotic ARC protein) and promotes its proteasomal degradation. This requires a functioning MDM2 RING finger domain. Oxidative stress reduces ARC levels and upregulates MDM2; MDM2 KO fibroblasts show defective ARC degradation rescuable by MDM2 re-expression. Co-immunoprecipitation, ubiquitination assays, MDM2 RING finger mutant (C464A), MDM2 KO fibroblasts with rescue, proteasome inhibitor treatment The Journal of biological chemistry High 17142834
2022 Arc directly antagonizes PSD-95 binding to TARPs (auxiliary subunits of AMPARs), acutely dispersing TARPs from PSD condensates formed via phase separation in a concentration-sensitive manner. TARPs with phosphorylated Ser in the 'P-S-Y' motif are refractory to Arc-mediated dispersal, indicating Arc cannot displace AMPARs from active synapses. Strengthening the Arc-TARP interaction enhances Arc's synapse-weakening capacity. Co-immunoprecipitation, phase separation assays with purified proteins, TARP phosphorylation mutagenesis, spine imaging with Arc overexpression Cell research High 35856091
2016 In skin-migratory dendritic cells (migDCs), Arc/Arg3.1 regulates actin dynamics through nonmuscle myosin II to drive accelerated DC migration during inflammation. Arc is required for DC migration critical for T cell responses in EAE and allergic contact dermatitis. Arc KO analysis, DC migration assays, nonmuscle myosin II activity assays, in vivo EAE and contact dermatitis models Science immunology Medium 28783680
2019 Arc/Arg3.1 expression in the NAc shell mediates reconsolidation of morphine-associated context memory by upregulating membrane GluR1 levels. This requires upstream ERK-CREB signaling as retrieval-induced increases in pERK1/2 and pCREB precede Arc induction and membrane GluR1 upregulation. Intra-NAc antisense ODN knockdown, western blot for membrane GluR1, MEK inhibitor U0126, morphine CPP behavioral paradigm The international journal of neuropsychopharmacology Medium 25746394
2019 Arc/Arg3.1 is translated locally in sensory neuron afferents in the skin in response to inflammatory cues. Arc-deficient mice display exaggerated vasodilation in response to inflammatory challenge, and this is rescued by injection of Arc-containing extracellular vesicles (EVs), indicating intercellular Arc signaling constrains neurogenic inflammation. Ribosome profiling (nascent translation), Arc KO mice, paw temperature/vasodilation measurements, EV rescue experiment in skin The Journal of neuroscience Medium 34326146
2019 Arc/Arg3.1 is induced by heat shock stress and negatively regulates the heat shock response (HSR) by binding to HSF1 and inhibiting its binding to heat shock elements in gene promoters, reducing Hsp27 and Hsp70 induction. This occurs without affecting HSF1 phosphorylation or nuclear localization. Arc is degraded by the ubiquitin-proteasome system with a half-life of <30 min after heat shock. Arc overexpression, Co-immunoprecipitation of Arc with HSF1, chromatin immunoprecipitation (ChIP) for HSF1 binding to HSEs, mRNA and protein quantification, proteasome inhibitor treatment Scientific reports Medium 30796345
2017 Arc interacts with dynamic chromatin and associates with histone markers for active enhancers (H3K27Ac) and active transcription (H3K9Ac). Knockdown of Arc alters expression of over 1900 genes including synaptic, plasticity, excitability, and Alzheimer's disease-associated genes in hippocampal neurons. ChIP-seq for histone marks, shRNA knockdown of Arc, microarray/transcriptomic analysis, Arc induction in HEK293T cells Biomedicines Medium 36009494
2004 Muscarinic acetylcholine receptor (mAChR) stimulation induces Arc expression through M1/M3 subtypes via protein kinase C (PKC) and Src family tyrosine kinases as key downstream signaling molecules. Pharmacological agonist/antagonist treatment in SH-SY5Y cells and rat brain, subtype-specific antagonists, PKC and Src kinase inhibitors, mRNA quantification Brain research. Molecular brain research Medium 14969744
2020 Arc is required for multiple behavioral and molecular responses to sleep deprivation: Arc KO mice show blunted sleep rebound, attenuated GluA1/pGluA1 increases in synaptoneurosomes after sleep deprivation, and suppressed SD-response gene induction. Arc protein expression changes subcellular location (nucleus, cytoplasm, synapse) with sleep/wake cycles. Arc KO mice, polysomnography, subcellular fractionation for GluA1/pGluA1, gene expression profiling, immunostaining for subcellular Arc localization Proceedings of the National Academy of Sciences of the United States of America Medium 32350140

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2006 Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 633 17088213
2006 Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking. Neuron 629 17088211
2008 The immediate early gene arc/arg3.1: regulation, mechanisms, and function. The Journal of neuroscience : the official journal of the Society for Neuroscience 414 19005037
2011 New views of Arc, a master regulator of synaptic plasticity. Nature neuroscience 400 21278731
2008 Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate. Neuron 397 18614031
2007 Sustained Arc/Arg3.1 synthesis controls long-term potentiation consolidation through regulation of local actin polymerization in the dentate gyrus in vivo. The Journal of neuroscience : the official journal of the Society for Neuroscience 386 17898216
2009 The Arc of synaptic memory. Experimental brain research 371 19690847
1999 Composite co-activator ARC mediates chromatin-directed transcriptional activation. Nature 363 10235267
2006 Increased expression of the immediate-early gene arc/arg3.1 reduces AMPA receptor-mediated synaptic transmission. Neuron 328 17088212
2011 Arc in synaptic plasticity: from gene to behavior. Trends in neurosciences 301 21963089
2012 Inverse synaptic tagging of inactive synapses via dynamic interaction of Arc/Arg3.1 with CaMKIIβ. Cell 253 22579289
2008 Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential for synapse-to-nucleus signaling in activated neurons. Proceedings of the National Academy of Sciences of the United States of America 220 19116276
2008 The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is required for memory consolidation of pavlovian fear conditioning in the lateral amygdala. The Journal of neuroscience : the official journal of the Society for Neuroscience 176 19020031
2011 Arc/Arg3.1 regulates an endosomal pathway essential for activity-dependent β-amyloid generation. Cell 173 22036569
2011 Activity-induced Notch signaling in neurons requires Arc/Arg3.1 and is essential for synaptic plasticity in hippocampal networks. Neuron 170 21315255
2010 Arc-dependent synapse-specific homeostatic plasticity. Proceedings of the National Academy of Sciences of the United States of America 146 21187403
2017 Arc protein: a flexible hub for synaptic plasticity and cognition. Seminars in cell & developmental biology 138 28890419
2013 Arc in the nucleus regulates PML-dependent GluA1 transcription and homeostatic plasticity. Nature neuroscience 122 23749147
2010 A specific requirement of Arc/Arg3.1 for visual experience-induced homeostatic synaptic plasticity in mouse primary visual cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 119 20505084
2016 Genetic Disruption of Arc/Arg3.1 in Mice Causes Alterations in Dopamine and Neurobehavioral Phenotypes Related to Schizophrenia. Cell reports 100 27524619
2007 Actin polymerization and ERK phosphorylation are required for Arc/Arg3.1 mRNA targeting to activated synaptic sites on dendrites. The Journal of neuroscience : the official journal of the Society for Neuroscience 98 17715342
2010 Time-dependent expression of Arc and zif268 after acquisition of fear conditioning. Neural plasticity 97 20592749
2013 Arc/Arg3.1 is a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum. Neuron 93 23791196
2013 Experience-induced Arc/Arg3.1 primes CA1 pyramidal neurons for metabotropic glutamate receptor-dependent long-term synaptic depression. Neuron 84 24094104
2015 Long-delayed expression of the immediate early gene Arc/Arg3.1 refines neuronal circuits to perpetuate fear memory. The Journal of neuroscience : the official journal of the Society for Neuroscience 78 25589774
2009 Arachidonic acid, ARC channels, and Orai proteins. Cell calcium 77 19278724
2018 The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility. Neuron 76 29861284
2015 Localization and local translation of Arc/Arg3.1 mRNA at synapses: some observations and paradoxes. Frontiers in molecular neuroscience 76 25628532
2006 Ubiquitination and degradation of the anti-apoptotic protein ARC by MDM2. The Journal of biological chemistry 72 17142834
2004 ARC channels: a novel pathway for receptor-activated calcium entry. Physiology (Bethesda, Md.) 70 15546853
2015 A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)'s putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression. Frontiers in neuroscience 69 26321903
2019 Adolescent Alcohol Exposure Epigenetically Suppresses Amygdala Arc Enhancer RNA Expression to Confer Adult Anxiety Susceptibility. Biological psychiatry 67 30827484
2020 Arc/Arg3.1 function in long-term synaptic plasticity: Emerging mechanisms and unresolved issues. The European journal of neuroscience 63 32888346
2016 BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis. Scientific reports 63 26888068
2015 Arc is a flexible modular protein capable of reversible self-oligomerization. The Biochemical journal 62 25748042
2014 A role for dendritic mGluR5-mediated local translation of Arc/Arg3.1 in MEF2-dependent synapse elimination. Cell reports 62 24857654
2007 Arc/Arg3.1 translation is controlled by convergent N-methyl-D-aspartate and Gs-coupled receptor signaling pathways. The Journal of biological chemistry 61 17981809
2011 The activity-regulated cytoskeletal-associated protein (Arc/Arg3.1) is required for reconsolidation of a Pavlovian fear memory. The Journal of neuroscience : the official journal of the Society for Neuroscience 59 21562269
2007 STIM1 and the noncapacitative ARC channels. Cell calcium 56 17391754
2019 An ARC-Regulated IL1β/Cox-2/PGE2/β-Catenin/ARC Circuit Controls Leukemia-Microenvironment Interactions and Confers Drug Resistance in AML. Cancer research 53 30674535
2015 NAc Shell Arc/Arg3.1 Protein Mediates Reconsolidation of Morphine CPP by Increased GluR1 Cell Surface Expression: Activation of ERK-Coupled CREB is Required. The international journal of neuropsychopharmacology 51 25746394
2007 Activity-regulated cytoskeleton-associated protein Arc/Arg3.1 binds to spectrin and associates with nuclear promyelocytic leukemia (PML) bodies. Brain research 51 17466953
2004 Muscarinic acetylcholine receptor stimulation induces expression of the activity-regulated cytoskeleton-associated gene (ARC). Brain research. Molecular brain research 46 14969744
2017 Histone Hypervariants H2A.Z.1 and H2A.Z.2 Play Independent and Context-Specific Roles in Neuronal Activity-Induced Transcription of Arc/Arg3.1 and Other Immediate Early Genes. eNeuro 45 28856239
2018 Arc/Arg3.1 mediates a critical period for spatial learning and hippocampal networks. Proceedings of the National Academy of Sciences of the United States of America 44 30442670
2010 Platelet-derived growth factor-mediated induction of the synaptic plasticity gene Arc/Arg3.1. The Journal of biological chemistry 44 20452974
2017 Arc restores juvenile plasticity in adult mouse visual cortex. Proceedings of the National Academy of Sciences of the United States of America 42 28790183
2020 Arc silence aggravates traumatic neuronal injury via mGluR1-mediated ER stress and necroptosis. Cell death & disease 40 31919348
2017 Inverse synaptic tagging: An inactive synapse-specific mechanism to capture activity-induced Arc/arg3.1 and to locally regulate spatial distribution of synaptic weights. Seminars in cell & developmental biology 40 28939038
2013 Hippocampal Arc (Arg3.1) expression is induced by memory recall and required for memory reconsolidation in trace fear conditioning. Neurobiology of learning and memory 40 23872190
2021 An mPOA-ARCAgRP pathway modulates cold-evoked eating behavior. Cell reports 39 34380037
2018 The Arc of cognition: Signaling cascades regulating Arc and implications for cognitive function and disease. Seminars in cell & developmental biology 38 29559111
2014 Arthrogryposis-renal dysfunction-cholestasis (ARC) syndrome: from molecular genetics to clinical features. Italian journal of pediatrics 38 25239142
2017 Regulation of spine structural plasticity by Arc/Arg3.1. Seminars in cell & developmental biology 37 28943393
2009 Fluorescent Arc/Arg3.1 indicator mice: a versatile tool to study brain activity changes in vitro and in vivo. Journal of neuroscience methods 37 19628007
2016 Arc/Arg3.1 governs inflammatory dendritic cell migration from the skin and thereby controls T cell activation. Science immunology 36 28783680
2015 Enhancement of dynamin polymerization and GTPase activity by Arc/Arg3.1. Biochimica et biophysica acta 35 25783003
2008 Midazolam reverses salicylate-induced changes in brain-derived neurotrophic factor and arg3.1 expression: implications for tinnitus perception and auditory plasticity. Molecular pharmacology 35 18524887
2014 A fine balance: Regulation of hippocampal Arc/Arg3.1 transcription, translation and degradation in a rat model of normal cognitive aging. Neurobiology of learning and memory 34 25151943
2017 Palmitoylation and Membrane Binding of Arc/Arg3.1: A Potential Role in Synaptic Depression. Biochemistry 33 29264923
2018 Sleep loss disrupts Arc expression in dentate gyrus neurons. Neurobiology of learning and memory 32 29635031
2017 The mechanistic link between Arc/Arg3.1 expression and AMPA receptor endocytosis. Seminars in cell & developmental biology 32 28890421
2017 Transcriptional and post-translational regulation of Arc in synaptic plasticity. Seminars in cell & developmental biology 32 28890422
2010 LTP- and LTD-inducing stimulations cause opposite changes in arc/arg3.1 mRNA level in hippocampal area CA1 in vivo. Hippocampus 32 20824728
2016 Late Arc/Arg3.1 expression in the basolateral amygdala is essential for persistence of newly-acquired and reactivated contextual fear memories. Scientific reports 31 26880136
2022 Arc Regulates Transcription of Genes for Plasticity, Excitability and Alzheimer's Disease. Biomedicines 30 36009494
2017 GSK3α and GSK3β Phosphorylate Arc and Regulate its Degradation. Frontiers in molecular neuroscience 30 28670266
2022 Arc weakens synapses by dispersing AMPA receptors from postsynaptic density via modulating PSD phase separation. Cell research 29 35856091
2013 Differential activation of amygdala Arc expression by positive and negatively valenced emotional learning conditions. Frontiers in behavioral neuroscience 29 24367308
2017 Arc ubiquitination in synaptic plasticity. Seminars in cell & developmental biology 28 28890418
2021 ARCGHR Neurons Regulate Muscle Glucose Uptake. Cells 27 34063647
2019 Activity-regulated cytoskeleton-associated protein (Arc/Arg3.1) regulates anxiety- and novelty-related behaviors. Genes, brain, and behavior 27 30761730
2018 Position- and Time-Dependent Arc Expression Links Neuronal Activity to Synaptic Plasticity During Epileptogenesis. Frontiers in cellular neuroscience 27 30154698
2012 STIM and Orai proteins and the non-capacitative ARC channels. Frontiers in bioscience (Landmark edition) 27 22201777
2021 Intercellular Arc Signaling Regulates Vasodilation. The Journal of neuroscience : the official journal of the Society for Neuroscience 26 34326146
2020 Lactate enhances Arc/arg3.1 expression through hydroxycarboxylic acid receptor 1-β-arrestin2 pathway in astrocytes. Neuropharmacology 26 32294462
2020 Loss of Arc attenuates the behavioral and molecular responses for sleep homeostasis in mice. Proceedings of the National Academy of Sciences of the United States of America 26 32350140
2004 MGluRs regulate the expression of neuronal calcium sensor proteins NCS-1 and VILIP-1 and the immediate early gene arg3.1/arc in the hippocampus in vivo. Biochemical and biophysical research communications 26 15336574
2022 Molecular physiology of Arc/Arg3.1: The oligomeric state hypothesis of synaptic plasticity. Acta physiologica (Oxford, England) 25 36073248
2021 Role of apoptosis repressor with caspase recruitment domain (ARC) in cell death and cardiovascular disease. Apoptosis : an international journal on programmed cell death 25 33604728
2017 Glutamate-induced rapid induction of Arc/Arg3.1 requires NMDA receptor-mediated phosphorylation of ERK and CREB. Neuroscience letters 25 28919534
2014 Tau pathology does not affect experience-driven single-neuron and network-wide Arc/Arg3.1 responses. Acta neuropathologica communications 25 24915991
2005 Early socio-emotional experience induces expression of the immediate-early gene Arc/arg3.1 (activity-regulated cytoskeleton-associated protein/activity-regulated gene) in learning-relevant brain regions of the newborn chick. Neuroscience 25 15908132
2017 Arc - An endogenous neuronal retrovirus? Seminars in cell & developmental biology 24 28941877
2013 Changes in the Egr1 and Arc expression in brain structures of pentylenetetrazole-kindled rats. Pharmacological reports : PR 24 23744421
2020 GSK3-ARC/Arg3.1 and GSK3-Wnt signaling axes trigger amyloid-β accumulation and neuroinflammation in middle-aged Shugoshin 1 mice. Aging cell 23 32857910
2009 Selective survival and maturation of adult-born dentate granule cells expressing the immediate early gene Arc/Arg3.1. PloS one 23 19290048
2013 Taste familiarity is inversely correlated with Arc/Arg3.1 hemispheric lateralization. The Journal of neuroscience : the official journal of the Society for Neuroscience 22 23843540
2019 The activity-regulated cytoskeleton-associated protein, Arc/Arg3.1, influences mouse cocaine self-administration. Pharmacology, biochemistry, and behavior 20 31682894
2016 Rare mutations and hypermethylation of the ARC gene associated with schizophrenia. Schizophrenia research 20 27464451
2010 Nociceptive stimulation induces expression of Arc/Arg3.1 in the spinal cord with a preference for neurons containing enkephalin. Molecular pain 20 20653942
2009 Altered expression and modulation of activity-regulated cytoskeletal associated protein (Arc) in serotonin transporter knockout rats. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 20 19576731
2008 ARG3.1/ARC expression in hippocampal dentate gyrus astrocytes: ultrastructural evidence and co-localization with glial fibrillary acidic protein. Journal of cellular and molecular medicine 20 18419604
2020 The continuing arc toward phototropic enlightenment. Journal of experimental botany 19 31907539
2020 RNF216 mediates neuronal injury following experimental subarachnoid hemorrhage through the Arc/Arg3.1-AMPAR pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 19 32918771
2016 Developmental Exposure to Cocaine Dynamically Dysregulates Cortical Arc/Arg3.1 Modulation in Response to a Challenge. Neurotoxicity research 19 27832448
2014 Fear extinction requires Arc/Arg3.1 expression in the basolateral amygdala. Molecular brain 19 24758170
2010 Arc/Arg3.1 mRNA global expression patterns elicited by memory recall in cerebral cortex differ for remote versus recent spatial memories. Frontiers in integrative neuroscience 19 20577636
2019 Activity-Regulated Cytoskeleton-Associated Protein (Arc/Arg3.1) is Transiently Expressed after Heat Shock Stress and Suppresses Heat Shock Factor 1. Scientific reports 18 30796345
2014 Association between DNA repair genes (XPD and XRCC1) polymorphisms and susceptibility to age-related cataract (ARC): a meta-analysis. Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie 18 24906341

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