Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2

daSilva, Luis L. P.; Wall, Mark J.; Almeida, Luciana Previato de; Wauters, Sandrine; Januário, Yunan C; Müller, Jürgen; Corrêa, Sônia A.L.

doi:10.1523/eneuro.0144-15.2016

Cited by 80 publications

(99 citation statements)

References 53 publications

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“…In addition, Arc protein can be trafficked to the cell nucleus where it is reported to regulate the transcription of the AMPAR subunit, GluA1 19 . Arc regulates AMPAR internalization, in part, by recruiting clathrin-mediated endocytic machinery to the synapse 16,20 , thus promoting synapse weakening 21,22 .…”

Section: Introductionmentioning

confidence: 99%

“…[16][17][18] In addition, Arc protein can be trafficked to the cell nucleus where it is reported to regulate the transcription of the AMPAR subunit, GluA1. 19 Arc regulates AMPAR internalization, in part, by recruiting clathrinmediated endocytic machinery to the synapse, 16,20 thus promoting synapse weakening. 21,22 Arc expression is induced in a number of brain regions following emotionally relevant experiences, including exposure to novelty, 23,24 environmental enrichment 25 and stressful experiences.…”

Section: Introductionmentioning

confidence: 99%

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Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

Penrod

Kumar

Smith

et al. 2019

Genes Brain and Behavior

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The activity-regulated cytoskeleton-associated protein (Arc, also known as Arg3.1) regulates glutamatergic synapse plasticity and has been linked to neuropsychiatric illness; however, its role in behaviors associated with mood and anxiety disorders remains unclear. We find that stress upregulates Arc expression in the adult mouse nucleus accumbens (NAc) – a brain region implicated in mood and anxiety behaviors. Global Arc knockout mice have altered AMPAR-subunit surface levels in the adult NAc, and the Arc-deficient mice show reductions in anxiety-like behavior, deficits in social novelty preference, and anti-depressive-like behavior. Viral-mediated expression of Arc in the adult NAc of male, global Arc KO mice restores normal levels of anxiety-like behavior in the elevated plus maze. Consistent with this finding, viral-mediated reduction of Arc in the adult NAc reduces anxiety-like behavior in male, but not female, mice in the elevated plus maze. NAc-specific reduction of Arc also produced significant deficits in both object and social novelty preference tasks. Together our findings indicate that Arc is essential for regulating normal mood-and anxiety-related behaviors and novelty discrimination, and that Arc’s function within the adult NAc contributes to these behavioral effects.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

Penrod

Kumar

Smith

et al. 2019

Genes Brain and Behavior

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“…1C). For example, AP-2 participates in the endocytosis of both NMDA- and AMPA-type glutamate receptors from the post-synaptic plasma membrane, a key process for the regulation of synaptic strength and plasticity [30,31,32,33•]. …”

Section: Ap-2: Pre- and Post-synaptic Endocytosismentioning

confidence: 99%

“…C . AP-2 mediates endocytosis of receptors at the post-synaptic terminal [30,31,32,33•]. RE: recycling endosome.…”

Section: Figurementioning

confidence: 99%

Neuronal functions of adaptor complexes involved in protein sorting

Guardia¹,

Pace²,

Mattera³

et al. 2018

Current Opinion in Neurobiology

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Selective transport of transmembrane proteins to different intracellular compartments often involves the recognition of sorting signals in the cytosolic domains of the proteins by components of membrane coats. Some of these coats have as their key components a family of heterotetrameric adaptor protein (AP) complexes named AP-1 through AP-5. AP complexes play important roles in all cells, but their functions are most critical in neurons because of the extreme compartmental complexity of these cells. Accordingly, various diseases caused by mutations in AP subunit genes exhibit a range of neurological abnormalities as their most salient features. In this article, we discuss the properties of the different AP complexes, with a focus on their roles in neuronal physiology and pathology.

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“…Loss of function studies support a role for Arc in long-term potentiation (LTP) and long-term depression (LTD) of synaptic transmission and homeostatic synaptic scaling. These diverse responses are mediated by distinct Arc protein-protein interaction complexes in the postsynaptic dendritic compartment and the neuronal nucleus (Chowdhury et al, 2006;DaSilva et al, 2016;Korb et al, 2013;Nair et al, 2017;Okuno et al, 2012;Zhang et al, 2015). Thus, convergent lines of evidence support a role for Arc as a signaling hub protein and cell-autonomous organizer of synaptic plasticity .…”

Section: Introductionmentioning

confidence: 96%

Molecular determinants of Arc oligomerization and formation of virus-like capsids

Eriksen

Nikolaienko

Hallin

et al. 2019

Preprint

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Expression of activity-regulated cytoskeleton-associated protein (Arc) is critical for long-term synaptic plasticity, memory formation, and cognitive flexibility. The ability of Arc to self-associate and form virus-like capsid structures implies functionally distinct oligomeric states. However, the molecular mechanism of Arc oligomerization is unknown. Here, we identified a 28-amino-acid region necessary and sufficient for Arc oligomerization. This oligomerization region is located within the second coil of a predicted anti-parallel coiled-coil in the N-terminal domain (NTD). Using alanine scanning mutagenesis, we found a 7-amino-acid motif critical for oligomerization and Arc-mediated transferrin endocytosis in HEK cells. Intermolecular fluorescence lifetime imaging in hippocampal neurons confirmed selfassociation mediated by the motif. To quantify oligomeric size, we performed a single-molecule photobleaching analysis of purified Arc wild-type and mutant. This analysis revealed a critical role for the NTD motif in the formation of higher-order Arc oligomers (30-170 molecules). Moreover, assembly of higher-order wild-type Arc oligomers was significantly enhanced by addition of GFP RNA. Purified wild-type Arc formed virus-like capsids, as visualized by negative-stain EM, and was estimated by light scattering analysis to contain 40-55 Arc units. In contrast, mutant Arc formed a homogenous dimer population as demonstrated by single-molecule TIRF imaging, size-exclusion chromatography with multi-angle light scattering analysis, small-angle X-ray scattering analysis, and single-particle 3D EM reconstruction. Thus, the dimer appears to be the basic building block for assembly. Herein, we show that the NTD motif is essential for higher-order Arc oligomerization, assembly of virus-like capsid particles, and facilitation of oligomerization by exogenous RNA. SIGNIFICANCEArc protein is rapidly expressed in neurons in response to synaptic activity and plays critical roles in synaptic plasticity, postnatal cortical developmental, and memory. Arc has diverse molecular functions, which may be related to distinct oligomeric states of the protein. Arc has homology to retroviral Gag protein and self-assembles into retrovirus-like capsid structures that are capable of intercellular transfer of RNA. Here, we identified a motif in the N-terminal coiled-coil domain of mammalian Arc that mediates higher-order oligomerization and formation of virus-like capsids. The basic building block is the Arc dimer and exogenous RNA facilitates further assembly. The identified molecular determinants of Arc oligomerization will help to elucidate the functional modalities of Arc in the mammalian brain. Recent advances highlight a structural and functional relationship between Arc and retroviralGag polyprotein. Arc was identified in a computational search for domesticated retrotransposons harboring Gag-like protein domains (Campillos et al., 2006). Biochemical studies showed that mammalian Arc has a positively charged N-terminal domain (NTD) and a ne...

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Activity-Regulated Cytoskeleton-Associated Protein Controls AMPAR Endocytosis through a Direct Interaction with Clathrin-Adaptor Protein 2

Cited by 80 publications

References 53 publications

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

Activity‐regulated cytoskeleton‐associated protein (Arc/Arg3.1) regulates anxiety‐ and novelty‐related behaviors

Neuronal functions of adaptor complexes involved in protein sorting

Molecular determinants of Arc oligomerization and formation of virus-like capsids

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