trans

NEUROTRANSMITTERS IN NEMATODES 377
FIGURE 15.16 Diagram showing the interaction of ‘ivermectin resistance’ genes. Information on resistance to
the macrocyclic lactones (MLs) in nematodes is derived mostly from C. elegans. The entry of ivermectin into the
nematode is facilitated by sensory (amphidial) neurons on the head. Once the drug has gained entry across the
cuticle, it is then able to interact with the GluCl receptors. There are at least three different genes encoding for at
least three different GluCl subunits that form inhibitory ion channels on muscle of the pharynx, motor neurons
and other neurons, and in addition perhaps on the female reproductive tract. The neurons that possess the GluCl
channels connect via gap junctions that are made up of innexins, coded for by unc-7 and unc-8 genes. Thus the
inhibitory effect of ivermectin on the pharynx may be direct via the GluCl2 subunit, or indirect, via the GluCl3
and GluCl1 subunits on extrapharyngeal neurons, and may require that effect to be mediated across gap junctions
(unc-7 and unc-9) to the pharynx. Removal of ivermectin and other MLs from the body of the nematodes
appears to be mediated by p-glycoprotein excretion. The mode of action and genetics of resistance illustrates that
the development of resistance requires the simultaneous mutation of several genes to develop a high level of resistance.
Factors that increase the concentration of macrocyclic lactones in the nematode will increase susceptibility:
genes (unc-7 and unc-9) that increase the electrical effects of stimulation of the GluCl ion channel will increase
susceptibility, and the presence of genes coding for GluCl-subunits will increase susceptibility. Note that the
physiology and location of the target site determines how resistance genes may interact. For example the genes
unc-7 or unc-9 form gap junctions that are able to pass on potential changes (hyperpolarization) associated with
stimulation of GluCl1 and GluCl3 subunits in inhibitory channels.
avr-15) produced only a 13-fold increase in
resistance.
Figure 15.16 summarizes information relating
to the genetics of resistance to the macrocyclic
lactones in nematodes, and is derived mostly
from C. elegans. Entry of ivermectin into the
nematode may be facilitated by sensory (amphidial)
neurons on the head. Once the drug has
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS