ARC

Required for consolidation of synaptic plasticity as well as formation of long-term memory. Regulates endocytosis of AMPA receptors in response to synaptic activity. Required for homeostatic synaptic scaling of AMPA receptors. Plays a role in the regulati

Full Name

Activity Regulated Cytoskeleton Associated Protein

Function

Master regulator of synaptic plasticity that self-assembles into virion-like capsids that encapsulate RNAs and mediate intercellular RNA transfer in the nervous system. ARC protein is released from neurons in extracellular vesicles that mediate the transfer of ARC mRNA into new target cells, where ARC mRNA can undergo activity-dependent translation. ARC capsids are endocytosed and are able to transfer ARC mRNA into the cytoplasm of neurons. Acts as a key regulator of synaptic plasticity: required for protein synthesis-dependent forms of long-term potentiation (LTP) and depression (LTD) and for the formation of long-term memory. Regulates synaptic plasticity by promoting endocytosis of AMPA receptors (AMPARs) in response to synaptic activity: this endocytic pathway maintains levels of surface AMPARs in response to chronic changes in neuronal activity through synaptic scaling, thereby contributing to neuronal homeostasis. Acts as a postsynaptic mediator of activity-dependent synapse elimination in the developing cerebellum by mediating elimination of surplus climbing fiber synapses. Accumulates at weaker synapses, probably to prevent their undesired enhancement. This suggests that ARC-containing virion-like capsids may be required to eliminate synaptic material. Required to transduce experience into long-lasting changes in visual cortex plasticity and for long-term memory (By similarity).
Involved in postsynaptic trafficking and processing of amyloid-beta A4 (APP) via interaction with PSEN1 (By similarity).
In addition to its role in synapses, also involved in the regulation of the immune system: specifically expressed in skin-migratory dendritic cells and regulates fast dendritic cell migration, thereby regulating T-cell activation (By similarity).

Biological Process

Anterior/posterior pattern specification Source: Ensembl
Cell migration Source: UniProtKB
Cytoskeleton organization Source: UniProtKB
Dendritic spine morphogenesis Source: ARUK-UCL
Endocytosis Source: UniProtKB-KW
Endoderm development Source: Ensembl
Learning Source: Ensembl
Long-term memory Source: UniProtKB
Long-term synaptic potentiation Source: ARUK-UCL
Modulation of chemical synaptic transmission Source: UniProtKB
mRNA transport Source: UniProtKB
Positive regulation of AMPA receptor activity Source: GO_Central
Protein homooligomerization Source: UniProtKB
Regulation of cell morphogenesis Source: UniProtKB
Regulation of dendritic spine morphogenesis Source: ARUK-UCL
Regulation of long-term synaptic depression Source: UniProtKB
Regulation of long-term synaptic potentiation Source: UniProtKB
Regulation of neuronal synaptic plasticity Source: GO_Central
Regulation of postsynaptic neurotransmitter receptor internalization Source: Ensembl
Vesicle-mediated intercellular transport Source: UniProtKB

Cellular Location

Postsynaptic cell membrane; Early endosome membrane; Cytoskeleton; Extracellular vesicle membrane; Synapse; Postsynaptic density; Dendrite; Cell cortex; Dendritic spine; Acrosome. Forms virion-like extracellular vesicles that are released from neurons. Enriched in postsynaptic density of dendritic spines. Targeted to inactive synapses following interaction with CAMK2B in the kinase inactive state. Accumulation at weaker synapses may be required to prevent their undesired enhancement. Associated with the cell cortex of neuronal soma and dendrites (By similarity). Associated with the sperm tail (By similarity).

PTM

Palmitoylation anchors the protein into the membrane by allowing direct insertion into the hydrophobic core of the lipid bilayer.
Ubiquitinated by UBE3A, leading to its degradation by the proteasome, thereby promoting AMPA receptors (AMPARs) expression at synapses.
Phosphorylation at Ser-260 by CaMK2 prevents homooligomerization into virion-like capsids by disrupting an interaction surface essential for high-order oligomerization. Phosphorylation by CaMK2 inhibits synaptic activity.