Figure 1.

Selected nAChR-mediated proliferative and apoptosis signaling pathways. (A) Binding of ACh or nicotine to nAChRs induces the formation of the oligomeric complex, which consists of nAChR, β-arrestin, and Src; this complex activates Src. Activated Src triggers the MAP kinase pathway and induces the formation of the cyclin D1-Cdk4/6 complex, leading to the phosphorylation of Rb [23,27,28]. The hyperphosphorylation of Rb releases the transcription factor E2F1 on proliferation-related gene promotors, leading to S-phase entry. The MAP kinase pathway also induces binding between the Rb-E2F1 dimer and Raf-1. The sustained mitogenic signaling leads to the dissociation of Raf-1 and Rb, leaving free E2F1. The increased influx of Ca²⁺ by nAChRs causes ERK1/2 and MEKK1 activation, MEKK1 activates NF-κB, and cell proliferation is induced [21,24,25,26,29,30]. (B) nAChR causes phosphorylation of Bad and Bax, thereby inactivating them and preventing apoptosis. Overexpression of Bcl-2 and its activation by nAChRs induces cell survival. The PKC, Akt, PKA, and MAP kinase pathways mediate this signaling. Created with Biorender.com (accessed on 12 June 2023).