Arc (protein)

Arc, for activity-regulated cytoskeleton-associated protein (also known as Arg3.1), is a plasticity protein first characterized in 1995. Arc is a member of the is_associated_with::immediate-early gene (IEG) family, a rapidly activated class of genes functionally defined by their ability to be transcribed in the presence of is_associated_with::protein synthesis inhibitors. Arc is_associated_with::mRNA is localized to activated synaptic sites in an is_associated_with::NMDA receptor-dependent manner, where the newly translated protein is believed to play a critical role in learning and memory-related molecular processes. Arc is widely considered to be an important protein in neurobiology because of its activity regulation, localization, and utility as a marker for plastic changes in the brain. Dysfunctions in the production of Arc protein has been implicated as an important factor in understanding of various neurological conditions including: is_associated_with::Amnesia; is_associated_with::Alzheimer's disease; Autism spectrum disorders; and, is_associated_with::Fragile X syndrome. Along with other IEGs such as is_associated_with::zif268 and Homer 1a, Arc is also a significant tool for is_associated_with::systems neuroscience as illustrated by the development of the cellular compartment analysis of temporal activity by fluorescence in situ hybridization, or catFISH technique (see is_associated_with::fluorescent in situ hybridization).

Molecular Profile
The Arc gene, located on is_associated_with::chromosome 15 in the mouse, chromosome 7 in the rat, and chromosome 8 in the is_associated_with::human, is conserved across vertebrate species and has low sequence homology to spectrin, a cytoskeletal protein involved in forming the is_associated_with::actin cellular cortex. A number of promoter and enhancer regions have been identified that mediate activity-dependent Arc transcription: a serum response element (SRE; see is_associated_with::serum response factor) at ~1.5 kb upstream of the initiation site; a second SRE at ~6.5 kb; and a synaptic activity response element (SARE) sequence at ~7 kb upstream that contains binding sites for cyclic AMP response element-binding protein (CREB), myocyte enhancer factor 2 (MEF2), and SRF.

The 3' UTR of the mRNA contains a is_associated_with::cis-acting element required for the localization of Arc to neuronal dendrites, as well as sites for two is_associated_with::exon junction complexes (EJCs) that make Arc a natural target for is_associated_with::nonsense mediated decay (NMD). Also important for translocation of cytoplasmic Arc mRNA to activated synapses is an 11 nucleotide binding site for is_associated_with::heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2).

Once transported, the translated protein is 396 residues in length, with an is_associated_with::N-terminus located at amino acids 1-25, a is_associated_with::C-terminus at 155-396 (note that the spectrin homology located at 228-380 within the C-terminal), and a putative is_associated_with::coiled coil domain at amino acids 26-154. Additionally, the protein has binding sites for endophilin 3 and dynamin 2 at amino acids 89-100 and 195-214, respectively. While Arc mRNA is subject to degradation by NMD, the translated protein contains a is_associated_with::PEST sequence at amino acids 351-392, indicating is_associated_with::proteasome-dependent degradation. The translated protein can be visualized with an is_associated_with::immunoblot as a band at 55 kDa.

Knockouts
Arc is critical as a ubiquitous signaling factor in early embryonic development and is required for growth and patterning during is_associated_with::gastrulation. The first knockouts (KOs) for Arc were therefore incompatible with life. Subsequent efforts produced is_associated_with::homozygous knockout mice by targeting the entire Arc gene rather than portions of the coding region, eliminating dominant negative effects. These animals proved viable and exhibit no gross malformations in neuronal architecture, but express higher levels of the GluR1 subunit and increased miniature excitatory postsynaptic currents (mEPSCs) in addition to displaying deficiencies in is_associated_with::long-term memory.

Induction
Changes in Arc mRNA and/or protein are correlated with a number of behavioral paradigms including cued is_associated_with::fear conditioning, contextual fear conditioning, spatial memory, is_associated_with::operant conditioning, and inhibitory avoidance. The mRNA is notably upregulated following electrical stimulation in LTP-induction procedures such as high frequency stimulation (HFS), and is massively and globally induced by maximal electroconvulsive shock (MECS).

The Arc transcript is the first known IEG that is entirely dependent upon activation of the is_associated_with::mitogen-activated protein kinase or MAP kinase (MAPK) cascade, a pathway important for regulation of cell growth and survival. Extracellular signaling to neuronal dendrites activates postsynaptic sites to increase Arc levels through a wide variety of signaling molecules, including mitogens such as is_associated_with::epidermal growth factor (EGF), is_associated_with::nerve growth factor (NGF), and is_associated_with::brain-derived neurotrophic factor (BDNF), glutamate acting at NMDA receptors, dopamine through activation of the D1 receptor subtype, and is_associated_with::dihydroxyphenylglycine (DHPG). The common factor for these signaling molecules involves activation of cyclic-AMP and its downstream target is_associated_with::protein kinase A (PKA). As such, direct pharmacological activation of cAMP by forskolin or 8-Br-cAMP robustly increases Arc levels while H89, a PKA antagonist, blocks these effects as does further downstream blockade of is_associated_with::mitogen-activated protein kinase kinase [sic] (MEK). Note that the MAPK cascade is a signaling pathway involving multiple is_associated_with::kinases acting sequentially [MAPKKK--> MAPKK--> MAPK].

MAPK is able to enter the nucleus and perform its phosphotransferase activity on a number of gene regulatory components that have implications for the regulation of immediate-early genes. Several is_associated_with::transcription factors are known to be involved in regulating the Arc gene (see above), including is_associated_with::serum response factor (SRF), is_associated_with::CREB, is_associated_with::MEF2, and is_associated_with::zif268.

Trafficking
Following transcription, Arc mRNA is transported out of the nucleus and localized to neuronal dendrites and activated synapses, a process dependent on the 3' UTR, polymerization of is_associated_with::actin, and ERK phosphorylation. The mRNA (and aggregate protein) is carried along is_associated_with::microtubules radiating out from the nucleus by is_associated_with::kinesin (specifically KIF5) and likely translocated into is_associated_with::dendritic spines by the actin-based motor protein is_associated_with::myosin-Va. Arc has been shown to be associated with is_associated_with::polyribosomes at synaptic sites, and is translated in isolated synaptoneurosomal fractions in vitro indicating that the protein is likely locally translated in vivo.

Synaptically localized Arc protein interacts with is_associated_with::dynamin and endophilin, proteins involved in is_associated_with::clathrin-mediated is_associated_with::endocytosis, and facilitates the removal of AMPA receptors from the plasma membrane. Consistent with this, increased Arc levels reduce AMPA currents, while Arc KOs display increases in surface AMPA expression.

Database Information
- Mitocheck database with video data  on mitosis in Arc-silenced human cells.

- Ensembl Arc gene information.

- Arc gene in Mus musculus.