Figure 3.

Muscarinic and nicotinic receptor-coupled signal transduction pathways mediating MAPK activity and proliferation. Both Erk1/2 activity and cell proliferation are activated by cholinergic (ACh) stimulation of mAChRs. ACh binds to M3, leading to a G_q-protein-mediated activation of PLC, which hydrolyses PIP2 to IP3 and DAG, subsequently mobilizing Ca²⁺ from organellar stores, leading to activation of PKC. Both ACh-induced MAPK activity and proliferation are reduced by the PKC inhibitor H7, indicating that PKC activity appears to be one of the upstream events critical to MAPK activation. mAChR stimulation induces increases in [Ca²⁺]_i via both Ca²⁺ influx and mobilization from intracellular stores. Muscarinic stimulation of MAPK activity and proliferation is prevented both by BAPTA-AM and EGTA, demonstrating that elevation of [Ca²⁺]_i is essential, and may stimulate Pyk2 phosphorylation and activate the MAPK. Muscarinic stimulation of MAPK activity is effectively eliminated by the MAPK kinase (MEK) inhibitor PD98059. M2 and M4 may provide parallel pathways to MAPK activation via pertussis toxin-sensitive G_i-proteins and βγ subunits. ERKI/II (MAPK) can serve as a convergence site for multiple extracellular signals known to induce plasticity in mature neurons. The best documented activation of the MAPK cascade occurs via ligand binding to RTK. Activation of RTK recruits the Shc-Grb2-SOS1 complex, which in turn activates Ras. Ras induces MAPK activation via an evolutionarily conserved pathway, which includes Raf, MEK (MAPKK), and ERKI/II (MAPK) (MAPK cascade). ERKI/II is known to have both cytoplasmic and nuclear targets and can translocate to the nucleus to modulate transcription in neurons. The block of proliferation induction by the MEK inhibitor PD98059 suggests that MAPK plays a role in the induction phase of proliferation. MAPK can also be activated in neural progenitor cells via nAChRs which increase [Ca²⁺]_i, and may modulate the MAPK cascade via activation of a Ca²⁺-dependent tyrosine kinase (PYK2) or calmodulin (CaM).