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Arc, for ''activity-regulated cytoskeleton-associated protein'' (also known as Arg3.1), is a plasticity protein first characterized in 1995.〔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.〕〔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 Nat Acad Sci''. 6;92(12):57 34-38〕 Arc is a member of the immediate-early gene (IEG) family, a rapidly activated class of genes functionally defined by their ability to be transcribed in the presence of protein synthesis inhibitors. Arc mRNA is localized to activated synaptic sites in an NMDA receptor-dependent manner,〔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.〕〔Steward O, Worley PF (2001). “Selective targeting of newly synthesized Arc mRNA to active synapses requires NMDA receptor activation.” ''Neuron''. 30:227-240.〕 where the newly translated protein is believed to play a critical role in learning and memory-related molecular processes.〔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.〕 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;〔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.〕 Alzheimer's disease; Autism spectrum disorders; and, Fragile X syndrome. Along with other IEGs such as zif268 and Homer 1a, Arc is also a significant tool for systems neuroscience as illustrated by the development of the ''cellular compartment analysis of temporal activity by fluorescence in situ hybridization'', or catFISH technique〔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.〕〔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.〕 (see fluorescent in situ hybridization). ==Molecular Profile== The Arc gene, located on chromosome 15 in the mouse(), chromosome 7 in the rat(), and chromosome 8 in the human(), is conserved across vertebrate species and has low sequence homology to spectrin,〔 a cytoskeletal protein involved in forming the 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 serum response factor) at ~1.5 kb upstream of the initiation site;〔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.〕〔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.〕 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.〔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.〕 The 3' UTR of the mRNA contains a cis-acting element required for the localization of Arc to neuronal dendrites,〔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.〕 as well as sites for two exon junction complexes (EJCs)〔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.〕 that make Arc a natural target for nonsense mediated decay (NMD).〔Tange TO, Nott A, Moore MJ (2004). “The ever-increasing complexities of the exon junction complex.” ''Curr Op Cell Bio''. 16:279-284.〕 Also important for translocation of cytoplasmic Arc mRNA to activated synapses is an 11 nucleotide binding site for heterogeneous nuclear ribonucleoprotein A2 (hnRNP A2).〔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.〕 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.〔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.〕 Additionally, the protein has binding sites for endophilin 3 and dynamin 2 at amino acids 89-100 and 195-214, respectively.〔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.〕 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.〔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.〕 The translated protein can be visualized with an immunoblot as a band at 55 kDa. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Arc (protein)」の詳細全文を読む スポンサード リンク
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