Figure 2

Diagram depicting proliferative and survival signaling pathways in cells. In vitro, the homomeric and heteromeric nAChRs jointly stimulate the indicated signaling cascades. Yellow arrows indicate proliferative pathways triggered by nAChRs. This activation triggers the MAP kinase pathway, leading to DNA synthesis. Sustained mitogenic signaling induces to S-phase entry. Black arrows indicate nAChR survival and proliferation pathways triggered by intracellular calcium increases involving indirect activation of β-adrenergic receptor signaling, which in turn, induces activation of epidermal growth factor (EGF) receptor leading to the cascade indicated by blue arrows. α7 nAChR and heteromeric α-βnAChRs are activated by their agonists. Influx of Ca²⁺ and other cations through the nAChRs and voltage-gated Ca²⁺ channels trigger the release of adrenaline and noradrenalin. Adenylyl cyclase activation downstream of β-adrenergic receptors induce the cyclic AMP-protein kinase A (PKA)-CREB (cAMP response element-binding protein) pathway, transactivates epidermal growth factor receptor (EGFR) and induces the release of EGF, and perhaps another growth factors. The responsiveness of this pathway is enhanced by α7 nAChR-mediated activation of Ras through β-arrestin-dependent SRC signaling. In turn, the EGFR activates the Akt pathway and its downstream effectors, X-linked inhibitor of apoptosis protein (XIAP)-survivin and nuclear factor-κB (NF-κB).