| Abstract: | Moonlighting cholinesterases in non-synaptic cholinergic mechanisms The early phylogenetic and ontogenetic appearance of acetylcholine (ACh) and its cholinergic protein components render their possible functionalities, apart from purely neuronal ones, most likely. The capacities of cholinesterases (ChEs) to form large protein complexes opened wide functional fields for them. Already existent in stem cells, ChEs in cooperation with components of the cell matrix (ECM) promote cell differentiation, whereby their enzymatic activity is (at least partially) dispensable. This is independently supported by effects of inactive AChE protein exerted in non-neuronal cells, as well as the discovery of cholinesterase-like adhesion molecules (CLAMs). Therefore, much evidence supports the conclusion that the original functionalities of cholinesterases, and, more generally of cholinergic systems, are to be sought in cell-cell-communication. Here, these views were exemplified by some in vitro and in vivo model studies. In the vertebrate retina early differentiating amacrine cells co-regulate network formation. Similarly potent are cholinergic mechanisms during skeletogenesis. ACh accelerates bone formation, and ChEs not only regulate its concentration, but exert additional structural functions. As much convincing, a study on tadpoles documented that gut formation in Xenopus laevis depends strictly on the AChE protein, but not on its enzymatic activity. A full elucidation of ChE functionalities is essential, since a multitude of anticholinesterases (ChE inhibitors) are widely applied in public life (agriculture, health, security). It is timely that cholinergic research focuses on elucidation of non-synaptic ChEs, and on analyzing non-neuronal cholinergic systems (NNCS) in general. |
