Cholinergic receptor pathways involved in apoptosis, cell proliferation and neuronal differentiation

Rodrigo R Resende,Avishek Adhikari

doi:10.1186/1478-811x-7-20

Abstract

Acetylcholine (ACh) has been shown to modulate neuronal differentiation during early development. Both muscarinic and nicotinic acetylcholine receptors (AChRs) regulate a wide variety of physiological responses, including apoptosis, cellular proliferation and neuronal differentiation. However, the intracellular mechanisms underlying these effects of AChR signaling are not fully understood. It is known that activation of AChRs increase cellular proliferation and neurogenesis and that regulation of intracellular calcium through AChRs may underlie the many functions of ACh. Intriguingly, activation of diverse signaling molecules such as Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, protein kinase C and c-Src is modulated by AChRs. Here we discuss the roles of ACh in neuronal differentiation, cell proliferation and apoptosis. We also discuss the pathways involved in these processes, as well as the effects of novel endogenous AChRs agonists and strategies to enhance neuronal-differentiation of stem and neural progenitor cells. Further understanding of the intracellular mechanisms underlying AChR signaling may provide insights for novel therapeutic strategies, as abnormal AChR activity is present in many diseases.

Highlights

Acetylcholine (ACh) is an ancient signaling molecule, [1] and is present in both prokaryotes and eukaryotes [2,3,4]
Cellular proliferation induced by the M3 subtype is mediated by production of inositol triphosphate, [8,66] and nitric oxide [for a review see [200]], while the effects of the M2 subtype were dependent on concomitant activation of M1, promoting the release of E2 prostaglandin and arginase catabolism
Chromatin IP (ChIP) analysis of human non-small cell lung cancer (NSCLC) tumor samples demonstrated increased recruitment of E2F1 and Raf-1 to proliferative promoters like cdc6 and cdc25A. These results suggest that binding of β-arrestin to nAChRs is an early and critical event in the initiation of nicotine-induced mitogenesis

Summary

Introduction

Acetylcholine (ACh) is an ancient signaling molecule, [1] and is present in both prokaryotes and eukaryotes [2,3,4]. NGF and lysophosphatidate receptor signaling systems can interact to promote G protein-mediated activation of the Erk pathway [133] These observations are consistent with the notion that TrkA can utilize pertussis toxin-sensitive Gi/o proteins to activate Akt, thereby inhibiting Bad and stimulating the NFκB regulator, IKK, via Gαγ activation [137,138] to allow cell survival through the M3 subtype [83,139,140]. Cellular proliferation induced by the M3 subtype is mediated by production of inositol triphosphate, [8,66] and nitric oxide [for a review see [200]], while the effects of the M2 subtype were dependent on concomitant activation of M1, promoting the release of E2 prostaglandin and arginase catabolism These events are related to tumoral cell growth [66], and inhibition of caspases [79,83]. PKC regulates p42/p44 MAP kinase activation by muscarinic receptor agonists in neuronal progenitor cells [55]

Concluding remarks

Grando SA

41. Roman GC

72. Williams CL