Anthelmintics and ion-channels: after a puncture, use a patch.
Two of three major types of anthelminitic, the avermectins and the nicotinic agonists, exert their therapeutic effect by an action on ligand-gated membrane ion-channels of nematodes. The avermectins, such as ivermectin, open glutamategated chloride channels which have so far been found only in invertebrate preparations; nicotinic anthelmintics, like levamisole, selectively gate nematode nicotinic acetylcholine receptors. We describe recent advances in the knowledge of the molecular structure of these ion-channel receptors in nematodes. Because opening of the ion-channels by these two groups of anthelmintic generates currents across cell membranes of nematodes, we can use electrophysiological methods to examine properties of the channels, the mode of action of the anthelmintics, and changes in the receptors associated with anthelmintic resistance. We illustrate some of our observations on these receptors using a two micro-electrode current-clamp technique to monitor membrane resistance (the puncture); and then some observations using The patch-clamp technique to monitor currents through individual ion-channels (the patch). The receptors for the two major groups of anthelmintics may not be homogeneous. Even in a single membrane patch from one muscle cell, nematode nicotinic acetylcholine receptors show evidence of heterogeneity and the avermectins may have multiple sites-of-action. If separate independent recessive genes are involved in production of different receptor subtypes, and if each subtype has to change to allow the development of resistance by the whole nematode, then the probability of resistance developing would be smaller than for anthelminitics with a single site-of-action. The MISER (multiple independent sites-of-action evading resistance) concept favours the development and use of anthelminitics with more than one site-of-action.
Martin
R J
RJ
Department of Preclinical Veterinary Sciences, University of Edinburgh, U.K. R.J.Martin@ed.ac.uk
Murray
I
I
Robertson
A P
AP
Bjorn
H
H
Sangster
N
N
D000818:Animals; D000871:Anthelmintics / Q000494:pharmacology*; D004351:Drug Resistance / Q000502:physiology; D004594:Electrophysiology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D007473:Ion Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D008839:Microelectrodes; D009348:Nematoda / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D009815:Oesophagostomum / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000235:genetics / Q000502:physiology
D000871:Anthelmintics; D007473:Ion Channels; D011950:Receptors, Cholinergic