Functional genomics of nematode acetylcholinesterases

Abstract

Acetylcholine is the major excitatory neurotransmitter controlling motor activities in nematodes, and the enzyme which hydrolyses and inactivates acetylcholine, acetylcholinesterase, is thus essential for regulation of cholinergic transmission. Different forms of acetylcholinesterase are encoded by multiple genes in nematodes, and analysis of the pattern of expression of these genes in Caenorhabditis elegans suggests that they perform non-redundant functions. In addition, many parasitic species which colonise host mucosal surfaces secrete hydrophilic variants of acetylcholinesterase, although the function of these enzymes is still unclear. Acetylcholinesterases have a history as targets for therapeutic agents against helminth parasites, but anti-cholinesterases have been used much more extensively as pesticides, for example to control crop damage and ectoparasitic infestation of livestock. The toxicity associated with these compounds (generally organophosphates and carbamates) has led to legislation to withdraw them from the market or restrict their use in many countries. Nevertheless, acetylcholinesterases provide a good example of a neuromuscular target enzyme in helminth parasites, and it may yet be possible to develop more selective inhibitors. In this article, we describe what is known about the structure and function of vertebrate cholinesterases, illustrate the molecular diversity and tissue distribution of these enzymes in C. elegans, and discuss to what extent this may represent a paradigm for nematodes in general.

The genomic basis of nematode parasitism

“…The role of parasitic nematode-produced acetylcholinesterases in the parasitic lifestyle is also not fully understood. In some species of gastrointestinal parasitic nematodes these molecules are secreted into the host gut where they have been thought to play a role in modulating the activity of the gut-including its muscular contraction and secretion of mucus and other fluid-with this facilitating parasite survival [37]. However, more recently, evidence points to parasite acetylcholinesterases having an immunoregulatory role [38].…”

Acetylcholinesterases of blood-feeding flies and ticks

“…Preliminary results suggest the presence of AChE enzymatic activity in tick saliva. AChE is known to be secreted by other parasites [22,23], including the saliva of blood feeding insects [24,25]. AChE is known to be involved in vertebrate immune function [26,27], and secretion of AChE in tick saliva may be involved in promoting feeding by hydrolyzing platelet activating factor [24], or inhibiting infiltration of lymphocytes [28] and wound healing [29] by reducing local tissue concentration of acetylcholine.…”

Ion channels and receptor as targets for the control of parasitic nematodes

“…Inhibition of this enzyme therefore causes a spastic paralysis through enhancing Ach activity and this has been exploited not only in the development of pesticides and anthelmintics, but also nerve gases (Martin, 1997). Organophosphates, such as dichlorvos and halaxon, and carbamates have been used to control plant and animal parasitic nematodes (Selkirk et al, 2005) and act by covalently modifying the active site of the enzyme. Perhaps not surprisingly, these compounds have safety problems and they are now little used for treating parasitic nematode infections.…”

“…However, it may still be possible to produce selective inhibitors of nematode AChEs. A very interesting variant form of AChE is that secreted by many parasitic nematodes, especially those that colonize mucosal surfaces within the gastro-intestinal tract (Ogilvie et al, 1973;Selkirk et al, 2005). N. brasiliensis secretes three such enzymes (Hussein et al, 1999(Hussein et al, , 2002a, Dictyocaulus viviparous secretes at least two (Lazari et al, 2003), Trichostrongylus colubriformis and Necator americanus at least one (Griffiths and Pritchard, 1994;Pritchard et al, 1994).…”