Fig. 7.

Regulation pathways of Arc transcription in BDNF- and Ca²⁺-mediated signaling. A). BDNF-mediated Arc expression is controlled through MAPK pathway and gated by intracellular calcium. Upon the activation of TrkB by BDNF, Ras-Raf-MAPK, PI3K, and PLC-γsignaling pathways are stimulated. It appeared that they are independent, no cross talk was identified among them in BDNF-stimulated neurons, and MAPK signaling is the sole regulator for Arc transcription. In addition, [Ca²⁺]_i regulates Arc transcription in parallel to MAPK. Furthermore, CaM may regulate Arc transcription through Ras-Raf-MAPK, but is independent of [Ca²⁺]_i and not through CaMKs. B) Ca²⁺-mediated Arc transcription requires MAPK, PI3K, extracellular Ca²⁺, intracellular Ca²⁺, CaM, and CaMK activity. It appeared that PI3K and CaMK regulated Arc transcription through ERK. Although a transient influx of extracellular Ca²⁺ is required for ERK activation, [Ca²⁺]_i is not required for ERK activation. Even with the activation of ERK, chelation of [Ca²⁺]_i blocks Arc up-regulation. This implicates that ERK and [Ca²⁺]_i are also parallel pathways in KCl-stimulated neurons. “?” indicates that the mechanism is unknown.