The Cholinergic ‘Pitfall’: Acetylcholine, a Universal Cell Molecule in Biological Systems, Including Humans

Abstract

1. Acetylcholine (ACh) represents one of the most exemplary neurotransmitters. In addition to its presence in neuronal tissue, there is increasing experimental evidence that ACh is widely expressed in pro- and eukaryotic non-neuronal cells. Thus, ACh has been detected in bacteria, algae, protozoa, tubellariae and primitive plants, suggesting an extremely early appearance of ACh in the evolutionary process. 2. In humans, ACh and/or the synthesizing enzyme, choline acetyltransferase, has been demonstrated in epithelial cells (airways, alimentary tract, urogenital tract, epidermis), mesothelial (pleura, pericardium) and endothelial and muscle cells. In addition, immune cells express the non-neuronal cholinergic system (i.e. the synthesis of ACh can be detected in human leucocytes (granulocytes, lymphocytes and macrophages)), as well as in rat microglia in vitro. 3. The widespread expression of non-neuronal ACh is accompanied by the ubiquitous expression of cholinesterase activity, which prevents ACh from acting as a classical hormone. 4. Non-neuronal ACh mediates its cellular actions in an auto- and paracrine manner via the activation of the widely expressed nicotinic and muscarinic acetylcholine receptors, which can interfere with virtually all cellular signalling pathways (ion channels and key enzymes). 5. Non-neuronal ACh appears to be involved in the regulation of basic cell functions, such as mitosis, cell differentiation, organization of the cytoskeleton, cell-cell contact, secretion and absorption. Non-neuronal ACh also plays a role in the regulation of immune functions. All these qualities together may mediate the so-called 'trophic property' of ACh. 6. Future experiments should be designed to analyse the cellular effects of ACh in greater detail. The involvement of the non-neuronal cholinergic system in the pathogenesis of chronic inflammatory diseases should be investigated to open up new therapeutic strategies.

Nicotine Strongly Activates Dendritic Cell–Mediated Adaptive Immunity

“…The nACh receptors are ligand-gated ionotropic channels consisting of ␣-subunits or a combination of ␣-and ␤-subunits, each of which has a unique pharmacological profile. 28 Intriguingly, we observed a marked expression of the homopentamer ␣ 7 -nACh receptor in DCs. The ␣ 7 -nACh receptor appears to play a crucial role in the observed effects of nicotine on DC maturation.…”

The Non-neuronal Cholinergic System

“…Figure 3 gives an example of positive ChAT immunoreactivity in human epithelial cells: human airway surface epithelium (basal, ciliated and goblet cells), submucosal glandular cells, small and large intestine, secretory cells of the femal breast, epidermal cells of the human skin, sebaceous and eccrine gland and kidney tubuli cells. Positive ChAT immunoreactivity and/or acetylcholine has also been detected in the epithelial cell layer of the buccal mucosa, esophagus, stomach (except the pyloric part), sigmoid, gallbladder, kidney plevis, urinary bladder, vaginal mucosa, cornea, amnion and placenta (1,3,4). In addition ChAT immunoreactivity and/ or acetylcholine have been found in human mesothelial cells (pleura, pericardium), endothelial cells, circulating cells (leukocytes, platelets), astrocytes, sperm, hair, nail, fat tissue and muscle cells (2,3,5).…”

“…For example, in mammals, acetylcholine can be synthesized by carnitine acetyltransferase which is expressed in mammalian heart and skeletal muscle (25,26). The following factors have been described to increase ChAT expression in neuronal tissue: activators of protein kinase A or cyclic AMP analogs, nerve growth factor, ciliary neurotrophic factor, leukemia inhibitory factor and retinoids; additionally, sex hormones and glucocorticoids can regulate ChAT gene expression and/ or ChAT enzyme activity (1,3,4,19,21).…”

The Ubiquity Nature of Acetylcholine

“…At the vascular wall the ACh produced by the endothelium acts through the auto-paracrine fashion in the intrinsic intima [5]. All the neuronal components, ACh, ChAT and VAChT and AChE above mentioned, are also present in the NNCS [9].…”