Diagram depicting apoptotic pathways modulated by nAChRs and mAChRs in neuronal progenitor cells. See text for a better description.

Calcium signaling pathways in stem cells and neural progenitor cells. Left panel represents a embryonic or adult stem cells and right panel the neuronal progenitor cells. Ca²⁺ signaling depends on the increase of the intracellular Ca²⁺ levels [Ca²⁺]_i, derived from extracellular calcium (Ca²⁺)_o sources or intracellular stores of the endoplasmic reticulum (ER Ca²⁺). It can enter through calcium channels operated by voltage (voltage-operated Ca²⁺ channels, VOCCs) in excitable cells such as neurons and muscular cells, or through calcium channels operated by receptors (receptor-operated Ca²⁺ channels, ROCs) in response to neurotransmitters. SOC's (store-operated Ca²⁺ channels, SOCs), open when internal Ca²⁺ stores are empty, and are generally present in non-excitable cells. Calcium from the ER is released by two types of channels, Inositol 1,4,5-trisphosphate (IP3) channels and ryanodine channels. The first is present in both neural progenitor and stem cells, while the latter is expressed only in nural progenitor cells. IP3 is generated by the action of the enzyme PLC in phosphatidylinositol 4,5-bisphosphate (PIP2). IP3 acts on receptors in the endoplasmic reticulum, promoting the release of Ca²⁺ from ER stores. IP3PIP2.

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).

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).