Drug resistance and neurotransmitter receptors of nematodes: recent studies on the mode of action of levamisole.
Here we review recent studies on the mode of action of the cholinergic anthelmintics (levamisole, pyrantel etc.). We also include material from studies on the free living nematode Caenorhabditis elegans. The initial notion that these drugs act on a single receptor population, while attractive, has proven to be an oversimplification. In both free living and parasitic nematodes there are multiple types of nicotinic acetylcholine receptor (nAChR) on the somatic musculature. Each type has different (sometimes subtly so) pharmacological properties. The implications of these findings are: (1) combinations of anthelmintic that preferentially activate a broad range of nAChR types would be predicted to be more effective; (2) in resistant isolates of parasite where a subtype has been lost, other cholinergic anthelmintics may remain effective. Not only are there multiple types of nAChR, but relatively recent research has shown these receptors can be modulated; it is possible to increase the response of a parasite to a fixed concentration of drug by altering the receptor properties (e.g. phosphorylation state). These findings offer a potential means of increasing efficacy of existing compounds as an alternative to the costly and time consuming development of new anthelmintic agents.
Martin
R J
RJ
Department of Biomedical Sciences, Iowa State University, Ames, IA 50011, USA. rjmartin@iastate.edu
Verma
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S
Levandoski
M
M
Clark
C L
CL
Qian
H
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Stewart
M
M
Robertson
A P
AP
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000969:Antinematodal Agents / Q000378:metabolism / Q000494:pharmacology*; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004351:Drug Resistance / Q000502:physiology; D007814:Larva / Q000502:physiology; D007978:Levamisole / Q000378:metabolism / Q000494:pharmacology*; D008564:Membrane Potentials / Q000502:physiology; D009348:Nematoda / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism / Q000502:physiology*; D009479:Neuropeptides / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000662:veterinary; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000145:classification / Q000235:genetics / Q000378:metabolism; D017981:Receptors, Neurotransmitter / Q000187:drug effects* / Q000378:metabolism*
D000969:Antinematodal Agents; D009479:Neuropeptides; D011950:Receptors, Cholinergic; D017981:Receptors, Neurotransmitter; C073964:AF2 neuropeptide; D007978:Levamisole; D000255:Adenosine Triphosphate; D010770:Phosphotransferases; D017868:Cyclic AMP-Dependent Protein Kinases; D010744:Phosphoric Monoester Hydrolases