The Arc transcript is dependent upon activation of the 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 epidermal growth factor (EGF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF), glutamate acting at NMDA receptors, dopamine through activation of the D1 receptor subtype, and dihydroxyphenylglycine (DHPG). The common factor for these signaling molecules involves activation of 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 while H89, a PKA antagonist, blocks these effects as does further downstream blockade of mitogen-activated protein kinase kinase [sic] (MEK). Note that the MAPK cascade is a signaling pathway involving multiple 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 transcription factors are known to be involved in regulating the Arc gene (see above), including serum response factor (SRF), CREB, MEF2, and zif268.