The multiple biological roles of the cholinesterases

It is tacitly assumed that the biological role of acetylcholinesterase is termination of synaptic transmission at cholinergic synapses. However, together with its structural homolog, butyrylcholinesterase, it is widely distributed both within and outside the nervous system, and, in many cases, the role of both enzymes remains obscure. The transient appearance of the cholinesterases in embryonic tissues is especially enigmatic. The two enzymes' extra-synaptic roles, which are known as 'non-classical' roles, are the topic of this review. Strong evidence has been presented that AChE and BChE play morphogenetic roles in a variety of eukaryotic systems, and they do so either by acting as adhesion proteins, or as trophic factors. As trophic factors, one mode of action is to directly regulate morphogenesis, such as neurite outgrowth, by poorly understood mechanisms. The other mode is by regulating levels of acetylcholine, which acts as the direct trophic factor. Alternate substrates have been sought for the cholinesterases. Quite recently, it was shown that levels of the aggression hormone, ghrelin, which also controls appetite, are regulated by butyrylcholinesterase. The rapid hydrolysis of acetylcholine by acetylcholinesterase generates high local proton concentrations. The possible biophysical and biological consequences of this effect are discussed. The biological significance of the acetylcholinesterases secreted by parasitic nematodes is reviewed, and, finally, the involvement of acetylcholinesterase in apoptosis is considered.