Arc (protein)

2017-05-19T09:13:56Z

139.184.128.248: /* Induction */

{{Infobox_gene}}
[[Image:Dentate Arc (c3).JPG|thumb|250px|Arc immunohistochemical staining of the rat ([[Rattus norvegicus]]) dentate gyrus. Image shows Arc protein levels at one hour following inhibitory avoidance training and immediate, systemic injection of 3 mg/kg corticosterone.]]
'''Arc''', for '''''a'''ctivity-'''r'''egulated '''c'''ytoskeleton-associated protein'' (also known as Arg3.1), is a [[Neuroplasticity|plasticity]] protein first characterized in 1995.<ref name="Lyford">Lyford GL, Yamagata K, Kaufmann WE, Barnes CA, Sanders LK, Copeland NG, Worley PF (1995). “Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeletal-associated protein that is enriched in neuronal dendrites.” ''Neuron''. 14:433-445.</ref><ref name="Link">Link W, Konietzko U, Kauselmann G, Krug M, Schwanke B, Frey U, Kuhl D (1995). “Somatodendritic expression of an immediate early gene is regulated by synaptic activity.” ''Proc Natl Acad Sci USA''. 6;92(12):57 34-38</ref> Arc is a member of the [[immediate-early gene]] (IEG) family, a rapidly activated class of genes functionally defined by their ability to be [[Transcription (genetics)|transcribed]] in the presence of [[protein synthesis inhibitor]]s. Arc [[mRNA]] is localized to activated synaptic sites in an [[NMDA receptor]]-dependent manner,<ref name="Wallace">Wallace CS, Lyford GL, Worley PF, Steward O (1998). “Differential intracellular sorting of immediate early gene mRNAs depends on signals in the mRNA sequence.” ''J Neurosci''. 18:26-35.</ref><ref name="Steward NMDA">Steward O, Worley PF (2001). “Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation.” ''Neuron''. 30:227-240.</ref> where the newly [[Translation (genetics)|translated]] protein is believed to play a critical role in learning and memory-related molecular processes.<ref name="McIntyre">McIntyre CK, Miyashita T, Setlow B, Marjon KD, Steward O, Guzowski JF, McGaugh JL (2005). “Memory-influencing intra-basolateral amygdala drug infusions modulate expression of Arc protein in the hippocampus.” ''PNAS''. 102:10718-10723.</ref> 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: [[Amnesia]];<ref>Gautam A, Wadhwa R, Thakur MK. Involvement of hippocampal Arc in amnesia and
its recovery by alcoholic extract of Ashwagandha leaves. Neurobiol Learn Mem. 2013 Nov;106:177-84.</ref> [[Alzheimer's disease]]; [[Autism spectrum|Autism spectrum disorders]]; and, [[Fragile X syndrome]].<ref>{{cite news
| title = Arc protein 'could be key to memory loss', says study
| url = http://www.bbc.co.uk/news/health-22811691
| publisher = [[BBC News Online]]
| date = 2013-06-09
| accessdate = 2013-06-09
}}</ref> Along with other IEGs such as [[zif268]] and [[HOMER1|Homer 1a]], Arc is also a significant tool for [[systems neuroscience]] as illustrated by the development of the '''''c'''ellular compartment '''a'''nalysis of '''t'''emporal activity by '''f'''luorescence '''i'''n '''s'''itu '''h'''ybridization'', or catFISH technique<ref>Guzowski JF, McNaughton BL, Barnes CA, Worley PF (1999). "Environment-specific expression of the immediate-early gene Arc in hippocampal neuronal ensembles." ''Nature Neuroscience''. 2:1120-1124.</ref><ref>Vazdarjanova A, McNaughton BL, Barnes CA, Worley PF, Guzowski JF (2002). "Experience-dependent coincident expression of the effector immediate-early genes Arc and Homer 1a in hippocampal and neocortical neuronal networks." ''J Neurosci''. 1:10067-10071.</ref> (see [[fluorescent in situ hybridization]]).

==Molecular Profile==

The Arc gene, located on [[chromosome]] 15 in the [[House mouse|mouse]][http://www.ensembl.org/Mus_musculus/Gene/Summary?g=ENSMUSG00000022602], chromosome 7 in the [[Brown rat|rat]][http://www.ensembl.org/Rattus_norvegicus/Gene/Summary?g=ENSRNOG00000043465], and chromosome 8 in the [[human]][http://www.ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000198576], is conserved across vertebrate species and has low sequence homology to spectrin,<ref name="Lyford" /> a cytoskeletal protein involved in forming the [[actin]] cellular cortex. A number of [[Promoter (biology)|promoter]] and [[enhancer (genetics)|enhancer]] regions have been identified that mediate activity-dependent Arc transcription: a serum response element (SRE; see [[serum response factor]]) at ~1.5 kb upstream of the initiation site;<ref name="Waltereit">Waltereit R, Dammermann B, Wulff P, Scafidi J, Staubli U, Kauselmann G, Bundman M, Kuhl D (2001). “Arg3.1/Arc mRNA induction by Ca2+ and cAMP requires protein kinase A and mitogen-activated protein kinase/extracellular regulated kinase activation.” ''J Neurosci''. 21:5484-5493.</ref><ref name="Pintchovski">Pintchovski SA, Peebles CL, Kim HJ, Verdin E, Finkbeiner S (2009). "The serum response factor and a putative novel transcription factor regulate expression of the immediate-early gene Arc/Arg3.1 in neurons. ''J Neurosci''. 29:1525-37.</ref> a second SRE at ~6.5 kb;<ref name="Pintchovski"/> and a synaptic activity response element (SARE) sequence at ~7 kb upstream that contains binding sites for [[CREB|cyclic AMP response element-binding protein]] (CREB), [[MEF2|myocyte enhancer factor 2]] (MEF2), and SRF.<ref>Kawashima T, Okuno H, Nonaka M, chi-Morishima A, Kyo N, Okamura M, Takemoto-Kimura S, Worley PF, Bito H (2009). "Synaptic activity-responsive element in the Arc/Arg3.1 promoter essential for synapse-to-nucleus signaling in activated neurons." ''PNAS''. 106:316-21.</ref>

The [[three prime untranslated region|3' UTR]] of the mRNA contains a [[cis-acting]] element required for the localization of Arc to neuronal dendrites,<ref name="Kobayashi">Kobayashi H, Yamamoto S, Maruo T, Murakami F (2005) “Identification of a cis-acting element required for dendritic targeting of activity-regulated cytoskeleton-associated protein mRNA.” ''Eur J Neurosci''. 22:2977-2984.</ref> as well as sites for two [[exon junction complex]]es (EJCs)<ref name="Giorgi">Giorgi C, Yeo, GW, Stone ME, Katz DB, Burge C, Turrigiano G, Moore MJ (2007). “The EJC factor eIF4AIII modulates synaptic strength and neuronal protein expression.” ''Cell''. 130:179-191.</ref> that make Arc a natural target for [[nonsense mediated decay]] (NMD).<ref>Tange TO, Nott A, Moore MJ (2004). “The ever-increasing complexities of the exon junction complex.” ''Curr Op Cell Bio''. 16:279-284.</ref> Also important for translocation of cytoplasmic Arc mRNA to activated synapses is an 11 nucleotide binding site for [[heterogeneous nuclear ribonucleoprotein]] A2 (hnRNP A2).<ref>Gao Y, Tatavarty V, Korza G, Levin MK, Carson JH (2008). "Multiplexed dendritic targeting of alpha calcium calmodulin-dependent protein kinase II, neurogranin, and activity-regulated cytoskeleton-associated protein RNAs by the A2 pathway." ''Mol Biol Cell''. 19:2311-27.</ref>

Once transported, the translated protein is 396 residues in length, with an [[N-terminus]] located at amino acids 1-25, a [[C-terminus]] at 155-396 (note that the spectrin homology located at 228-380 within the C-terminal), and a putative [[coiled coil]] domain at amino acids 26-154.<ref>Bloomer WAC, VanDongen HMA, VanDongen AMJ (2007). “Activity-regulated cytoskeletal-associated protein Arc/Arg3.1 binds to spectrin and associates with nuclear promyelocytic leukemia (PML) bodies.” ''Brain Research''. 1153:20-33.</ref> Additionally, the protein has binding sites for endophilin 3 and dynamin 2 at amino acids 89-100 and 195-214, respectively.<ref name="Chowdhury">Chowdhury S, Shepherd JD, Okuno H, Lyford G, Petralia RS, Plath N, Kuhl D, Huganir RL, Worley PF (2006). “Arc/Arg3.1 interacts with the endocytotic machinery to regulate AMPA receptor trafficking.” ''Neuron''. 52:445-459.</ref> While Arc mRNA is subject to degradation by NMD, the translated protein contains a [[PEST sequence]] at amino acids 351-392, indicating [[proteasome]]-dependent degradation.<ref>Rao VR, Pintchovski SA, Chin J, Peebles CL, Mitra S, Finkbeiner S (2006). "AMPA receptors regulate transcription of the plasticity-related immediate-early gene Arc." ''Nat Neurosci''. 9:887-95.</ref> The translated protein can be visualized with an [[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 [[gastrulation]].<ref>Liu D, Bei D, Parmar H, Matus A (2000). “Activity-regulated, cytoskeleton-associated protein (Arc) is essential for visceral endoderm organization during early embryogenesis.” ''Mech Dev''. 92:207-215.</ref> The first [[gene knockout|knockouts]] (KOs) for Arc were therefore incompatible with life. Subsequent efforts produced [[homozygous]] knockout mice by targeting the entire Arc gene rather than portions of the coding region, eliminating [[dominance (genetics)|dominant negative]] effects. These animals proved viable and exhibit no gross malformations in neuronal architecture, but express higher levels of the [[AMPA receptor|GluR1 subunit]] and increased miniature [[excitatory postsynaptic potential|excitatory postsynaptic currents]] (mEPSCs) in addition to displaying deficiencies in [[long-term memory]].<ref>Plath N, Ohana O, Dammermann B, Errington ML, Schmitz D, Gross C, Mao X, Engelsberg A, Mahike C, Welzi H, Kobalz U, Stawrakakis A, Fernandez E, Walteriet R, Bick-Sander A, Therstappen E, Cooke SF, Blanquet V, Wurst W, Salmen B, Bosl MR, Lipp HP, Grant SGN, Bliss TVP, Wolfer DP, Kuhl D (2006). “Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories.” ''Neuron''. 52:437-444.</ref>

==Induction==

Changes in Arc mRNA and/or protein are correlated with a number of behavioral paradigms including cued [[fear conditioning]],<ref>Monti B, Berteotti C, Contestabile A (2006). “Subchronic rolipram delivery activates hippocampal CREB and Arc, enhances retention and slows down extinction of conditioned fear.” ''Neuropshychopharm''. 31:278-286.</ref> contextual fear conditioning,<ref>Huff NC, Frank M, Wright-Hardesty K, Sprunger D, Matus-Amat P, Higgins E, Rudy JW (2006). “Amygdala regulation of immediate-early gene expression in the hippocampus induced by contextual fear conditioning.” ''J Neurosci''. 26:1616-1623.</ref> spatial memory,<ref name="Guzowski">Guzowski JF, Lyford GL, Stevenson GD, Houston FP, McGaugh JL, Worley PF, Barnes CA (2000). “Inhibition of activity-dependent Arc protein expression in the rat hippocampus impairs maintenance of long-term potentiation and the consolidation of long-term memory.” ''J Neurosci''. 20:3993-4001.</ref><ref>Guzowski JF, Setlow B, Wagner EK, McGaugh JL (2001). “Experience-dependent gene expression in the rat hippocampus after spatial learning: a comparison of immediate-early genes Arc, c-fos, and zif268.” ''J Neurosci''. 21:5089-5098.</ref> [[operant conditioning]],<ref>Kelly MP, Deadwyler SA (2002). “Acquisition of a novel behavior induces higher levels of Arc mRNA than does overtrained performance.” ''Neuroscience''. 110:617-626.</ref><ref>Kelly MP, Deadwyler SA (2003). “Experience-dependent regulation of the immediate-early gene Arc differs across brain regions.” ''J Neurosci''. 23:6443-6451.</ref> and inhibitory avoidance.<ref name="McIntyre"/> The mRNA is notably upregulated following electrical stimulation in [[long-term potentiation|LTP]]-induction procedures such as high frequency stimulation (HFS),<ref name="Guzowski"/> and is massively and globally induced by maximal electroconvulsive shock (MECS).<ref name="Lyford"/><ref name="Wallace"/>

The Arc transcript is dependent upon activation of the [[mitogen-activated protein kinase]] or MAP kinase (MAPK) cascade,<ref name="Waltereit"/> a pathway important for regulation of cell growth and survival.<ref>Impey S, Obrietan K, Storm DR (1999). “Making new connections: role of ERK/MAP kinase signaling in neuronal plasticity.” ''Neuron''. 23:11-14.</ref> Extracellular signaling to neuronal dendrites activates postsynaptic sites to increase Arc levels through a wide variety of signaling molecules, including mitogens such as [[epidermal growth factor]] (EGF),<ref name="Lyford"/> [[nerve growth factor]] (NGF),<ref name="Lyford"/> and [[brain-derived neurotrophic factor]] (BDNF),<ref name="Giorgi"/> glutamate acting at NMDA receptors,<ref name="Wallace"/><ref name="Steward NMDA"/> dopamine through activation of the [[Dopamine receptor D1|D1 receptor subtype]],<ref>Granado N, Ortiz O, Suarez LM, Martin ED, Cena V, Solis JM, Moratalla R (2008). “D1 but not D5 dopamine receptors are critical for LTP, spatial learning, and LTP-induced Arc and zif268 expression in the hippocampus.” ''Cerebral Cortex''. 18:1-12.</ref><ref name="Bloomer">Bloomer WAC, VanDongen HMA, VanDongen AMJ (2008). “Arc/Arg3.1 translation is controlled by convergent N-methyl-D-aspartate and Gs-coupled receptor signaling pathways.” ''J Biol Chem''. 283:582-592.</ref> and [[dihydroxyphenylglycine]] (DHPG).<ref>Brackmann M, Zhao C, Kuhl D, Manahan-Vaughan D, Braunewell KH (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.” ''Biochem and Biophys Res Comm''. 322:1073-1079.</ref> The common factor for these signaling molecules involves activation of [[cyclic adenosine monophosphate|cyclic-AMP]] and its downstream target [[protein kinase A]] (PKA). As such, direct pharmacological activation of cAMP by forskolin or 8-Br-cAMP robustly increases Arc levels<ref name="Waltereit"/><ref name="Bloomer"/> while H89, a PKA antagonist, blocks these effects<ref name="Bloomer"/> as does further downstream blockade of [[mitogen-activated protein kinase kinase]] [sic] (MEK).<ref name="Waltereit"/> Note that the MAPK cascade is a signaling pathway involving multiple [[kinase]]s acting sequentially [MAPKKK--> MAPKK--> MAPK].

MAPK is able to enter the nucleus and perform its phosphotransferase activity on a number of gene regulatory components<ref>Treisman R (1996). “Regulation of transcription by MAP kinase cascades.” ''Curr Op Cell Biol''. 8:205-215.</ref> that have implications for the regulation of immediate-early genes. Several [[transcription factor]]s are known to be involved in regulating the Arc gene (see above), including [[serum response factor]] (SRF),<ref name="Waltereit"/><ref name="Kawashima">Kawashima T, Okuno H, Nonaka M, Adachi-Morishima A, Kyo N, Okamura M, Takemoto-Kimura S, Worley PF, Bito H (2009). “Synaptic activity response element in the Arc/Arg3.1 promoter essential for synapse-to-nucleus signaling in activated neurons.” ''PNAS''. 106:316-321.</ref> [[CREB]],<ref name="Kawashima"/> [[MEF2]],<ref name="Kawashima"/> and [[zif268]].<ref>Li L, Carter J, Gao X, Whitehead J, Tourtellotte WG (2005). “The neuroplasticity-associated Arc gene is direct transcriptional target of early growth response (Egr) transcription factors.” ''Mol and Cell Biol''. 25:10286-10300.</ref>

==Trafficking==

Following transcription, Arc mRNA is transported out of the nucleus and localized to neuronal dendrites<ref name="Lyford"/> and activated synapses,<ref>Steward O, Wallace CS, Lyford GL, Worley PF (1998). “Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites.” ''Neuron''. 21:741-751.</ref> a process dependent on the 3' UTR,<ref name="Kobayashi" /> polymerization of [[actin]],<ref name="Huang">Huang F, Chotiner JK, Steward O (2007). “Actin polymerization and ERK phosphorylation are required for Arc/Arg 3.1 mRNA targeting to activated synaptic sites on dendrites.” ''J Neurosci''. 27:9054-9067.</ref> and [[extracellular signal-regulated kinase|ERK]] phosphorylation.<ref name="Huang"/> The mRNA (and aggregate protein) is carried along [[microtubule]]s radiating out from the nucleus by [[kinesin]] (specifically KIF5)<ref>Kanai Y, Dohmae N, Hirokawa N (2004). “Kinesin transports RNA: isolation and characterization of an RNA-transporting granule.” ''Neuron''. 43:513-525.</ref> and likely translocated into [[dendritic spine]]s by the actin-based motor protein [[myosin]]-Va.<ref>Yoshimura A, Fujii R, Watanabe Y, Okabe S, Fukui K, Takumi T (2006). “Myosin-Va facilitates the accumulation of mRNA/protein complex in dendritic spines.” ''Curr Biol''. 16:2345-2351.</ref> Arc has been shown to be associated with [[polyribosome]]s at synaptic sites,<ref>Bagni C, Mannucci L, Dotti CG, Amaldi F (2000). “Chemical stimulation of synaptosomes modulates alpha-calcium/calmodulin dependent protein kinase II mRNA association to polysomes.” ''J Neurosci''. 20:1-6.</ref> and is translated in isolated synaptoneurosomal fractions<ref>Yin Y, Edelman GM, Vanderklish PW (2002). “The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes.” ''PNAS''. 99:2368-2373.</ref> ''in vitro'' indicating that the protein is likely locally translated ''in vivo''.

Synaptically localized Arc protein interacts with [[dynamin]] and endophilin, proteins involved in [[clathrin]]-mediated [[endocytosis]], and facilitates the removal of AMPA receptors from the plasma membrane.<ref name="Chowdhury"/> Consistent with this, increased Arc levels reduce AMPA currents,<ref>Rial Verde EM, Lee-Osbourne J, Worley PF, Malinow R, Cline HT (2006). “Increased expression of the immediate-early gene Arc/Arg3.1 reduces AMPA receptor-mediated synaptic transmission.” ''Neuron''. 52:461-474.</ref> while Arc KOs display increases in surface AMPA expression.<ref>Shepherd JD, Rumbaugh G, Wu J, Chowdhury S, Plath N, Kuhl D, Huganir RL, Worley PF (2006) “Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors.” ''Neuron''. 52:475-484.</ref>

==Database Information==

- Mitocheck database [http://www.mitocheck.org/cgi-bin/mtc?query=MCG_0007741&query_type=genes] with video data [http://www.mitocheck.org/cgi-bin/mtc?action=list_movies;query=MCO_0019700] on mitosis in Arc-silenced human cells.

- Ensembl Arc gene information [http://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000198576].

- Arc gene in Mus musculus [http://www.informatics.jax.org/searches/accession_report.cgi?id=MGI:88067].

==References==
{{reflist|30em}}

==External links==
* {{UCSC gene info|ARC}}

{{DEFAULTSORT:Arc (Protein)}}
[[Category:Proteins]]
[[Category:Molecular biology]]

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Arc (protein)