Figure 1. Regulation of Arc expression. Signaling through NMDARs [35], TrkB receptors [26,27] and group 1 metabotropic glutamate receptors (mGluRs) [29,30] promotes Arc transcription through one or several downstream signaling kinases, including protein kinase A (PKA) and extracellular-signal-regulated kinase (ERK). ERK acts through a coactivator, such as a ternary complex factor (TCF), to activate serum response factor (SRF), which binds a serum response element (SRE) in the Arc promoter to increase transcription [27,37]. ERK also acts through a Zeste-like factor, which binds a Zeste-like response element (ZRE) [27]. PKA acts near the SRF site through an unidentified enhancer element. The region surrounding the Arc gene also contains partial cAMP response element (CRE) and myocyte enhancer factor 2 (MEF2) sites [37] and CpG sites that mediate epigenetic modifications of Arc transcription [83]. Response elements (REs) in the promoter of Arc [27] and signaling pathways induced after AMPAR activation [32] inhibit transcription. ERK signaling and signaling pathways activated by NMDARs [47] and mGluR1s [30] promote Arc translation. Arc protein is ubiquitinated by ubiquitin-protein ligase E3A (UBE3A) [52], which targets it to the proteasome for degradation. Question marks indicate relationships for which the supporting evidence is limited or indirect, or has not been specifically linked to Arc expression. Abbreviations: cAMP, cyclic adenosine monophosphate; mAChR, muscarinic acetylcholine receptor; TrkB, tropomycin-receptor-kinase; mGluR1, metabotropic glutamate receptor; PKA, protein kinase A; PKC, protein kinase C; RE, repressor element; ZRE, Zeste-like response element; SRE, serum response element; MNK1, mitogen-activated protein kinase-interacting kinase 1; eIF4E, eukaryotic initiation factor 4E; eEF2K, eukaryotic elongation factor 2 kinase; eEF2, eukaryotic elongation factor 2; UBE3A, ubiquitin-protein ligase E3A; Ub, ubiquitin.