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SUMMARY
The macrocyclic lactones are the biggest selling and arguably most eective anthelmintics currently available. They are
good substrates for the P-glycoproteins, which might explain their selective toxicity for parasites over their vertebrate
hosts. Changes in the expression of these pumps have been implicated in resistance to the macrocyclic lactones, but it is
clear that they exert their anthelmintic eects by binding to glutamate-gated chloride channels expressed on nematode
neurones and pharyngeal muscle cells. This eect is quite distinct from the channel opening induced by glutamate, the
endogenous transmitter acting at these receptors, which produces rapidly opening and desensitising channels. Ivermectinactivated channels open very slowly but essentially irreversibly, leading to a very long-lasting hyperpolarisation or
depolarisation of the neurone or muscle cell and therefore blocking further function. Molecular and genetic studies have
shown that there are multiple GluCl isoforms in both free-living and parasitic nematodes : the exact genetic make-up and
functions of the GluCl may vary between species. The known expression patterns of the GluCl explain most of the observed
biological eects of treatment with the macrocyclic lactones, though the reason for the long-lasting inhibition of larval
production in larial species is still poorly understood.
Key words: Ivermectin, Caenorhabditis elegans, Haemonchus contortus, Filaria, ionotropic receptor, chemotherapy.
THE AVERMECTIN/MILBEMYCIN
ANTHELMINTICS
S86
S87
Table 1. The GluCl genes of Caenorhabditis elegans, and the subunits they encode
Gene
Subunits
Encoded
avr-14
GluCla3A
GluCla3B
avr-15
GluCla2A
GluCla2B
glc-1
GluCla1
glc-2
glc-3
glc-4
GluClb
GluCla4
?
Properties
References
S88
Properties
References
GluCla/GluCla
Haemonchus contortus
GluCla3A
GluCla3B
GluClb
Cooperia oncophora,
Haemonchus contortus
_
A
500 nA |__
10 s 10000 + nA
C. oncophora GluCl subunits are much more sensitive, with the a3 subunit forming a receptor with an
EC50 of y0.03 mM and the b subunit having a EC50
for glutamate of y0.18 mM (Njue et al. 2004). This
increased agonist sensitivity of the GluCl subunits
may be conserved in H. contortus, since the
HcGluCla subunit forms receptors with an EC50 for
glutamate of only 8.4 mM (Forrester et al. 2003) and
the HcGluCla3B receptor has a very similar quantitative pharmacology to that from C. oncophora
(Rogers & Wolstenholme, unpublished). By analogy
with the other members of the cys-loop family of
S89
EC50 Glutamate
V K L L L R R
30 M
C. oncophora IVMR
V K L F L R R
96 M
H. contortus
V K L L L R R
27 M
C. elegans
V V L R L R R
2.2 mM
D. immitis
V M L L L R R
~1 mM
A. suum
V K L L L R R
ND
C. oncophora IVM
S90
S91
Pharyngeal Neurones
Pharynx
Amphids
Commissure
Nerve Cords
Nerve Ring
Pharyngeal Muscle
Fig. 3. Schematic representation of the distribution of GluCl in nematodes. The cuticle is outlined in grey and the
pharynx in black. Structures reported to express GluCl are indicated by arrows.
ACKNOWLEDGEMENTS
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