trans

376 NEUROTRANSMITTERS
TABLE 15.3
Cloned GluCl subunits from parasitic nematodes
Species Clone Accession Other Closest Expression data 1
number name C. elegans gene
Haemonchus contortus Hc-gbr2A Y14233 HG2 avr-14 (gbr-2) Hc-gbr2B binds ivermectin.
Hc-gbr2B Y14234 HG3 Present in the nerve ring, on ventral
and dorsal nerve cords, the
anterior dorsal sublateral cord
and motor neuron commissures 2
H. contortus HcGluCl Y09796 HG4 glc-2 Does not bind ivermectin.
Expressed on motor neuron
commissures
H. contortus HcGluCl AF076682 HG5 avr-14 (gbr-2) 3 Binds ivermectin. Expressed at
AJ131347
higher levels in adults than
larvae. Present on motor neuron
commissures
Ascaris suum As-gbr2 Y18347 avr-14 (gbr-2) Present on nerve cords
Onchocerca volvulus GluClX U59745 avr-14 (gbr-2)
Onchocerca ochengi Putative AF054632 glc-1
-subunit
O. ochengi Putative AF054631 glc-2
-subunit
Dirofilaria immitis GluClX U59744 avr-14 (gbr-2)
1 Localization data obtained using immunofluorescence.
2 The antibody used did not distinguish between Hc-gbr2A and 2B.
3 The level of identity between this subunit and avr-14 is lower than for the Hc-gbr2, As-gbr2 and the GluClX
subunits.
be conserved in these species. The other H.
contortus GluCl gene is interesting because
it seems not to be orthologous with any of the
four C. elegans GluCl genes, as it shares about
55–60% sequence identity with all of them.
The H. contortus GluCl is expressed at higher
levels in adult worms than in larvae, suggesting
it may be most important in the parasitic
stages of the life cycle. This subunit binds ivermectin,
is found on motoneurons, and may be
an important target for the drug in vivo.
The H. contortus GluCl subunit, like its
C. elegans counterpart, does not bind ivermectin.
Though the pharmacology of the two
subunits is similar, their distribution may be
very different. The HcGluCl subunit is found
on motoneuron commissures in the anterior
region of the adult parasite, but the C. elegans
subunit is only found on pharyngeal muscle
cells. If this difference in localization is substantiated
by further studies, it may serve as
an important caution against making generalizations
among different species of nematodes.
Ivermectin resistance
We know from the studies of Dent that ivermectin
resistance in C. elegans involves the
genes avr-15, avr-14, glc-1, unc-7, unc-9 and dyf
(dye-filling defective). Simultaneous mutations
of the GluCl genes avr-15, avr-14 and glc-1
were required for the establishment of high
levels of immunity (4000). Little resistance
is seen with mutations in individual genes. A
combination of two of the genes (avr-14 and
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS