trans

NEUROTRANSMITTERS IN NEMATODES 375
muscle and in motoneurons of the nerve ring
and nerve cords. The avr-15-encoded subunit
(the long form) can form a homo-oligomeric
channel that is ivermectin-sensitive and
glutamate-gated when expressed in Xenopus
oocytes. The avr-14 subunits are expressed in
a subset of 40 extrapharyngeal neurons in the
ring ganglia of the head and motor neurons of
the ventral cord and mechanosensory neurons.
Glc-1 appears to be represented in the
extrapharyngeal neurons. The location of the
expressed glc-3 is not yet known. The GluCl
subunit was found on the pm4 pharyngeal
muscle cells of C. elegans.
Electrophysiology of glutamate and
ivermectin in nematode parasites
Avermectin-sensitive sites in A. suum have been
identified on pharyngeal muscle using currentclamp;
avermectins produce hyperpolarization
and an increase in Cl conductance when
applied onto pharyngeal preparations. Glutamate
and macrocyclic lactones (MLs) increase
the opening of expressed GluCl receptor channels
in Ascaris suum pharyngeal muscle. They
also increase opening of glutamate-gated chloride
channels found in the pharynx of Ascaris
suum (Figure 15.15).
FIGURE 15.15 Glutamate-activated single-channel
currents recorded from Ascaris pharynx using an
inside-out patch. Addition of ivermectin to the insideout
patch increases the opening of the channels.
The split chamber technique allows the selective
application of avermectin to the dorsal and
ventral halves of A. suum. Under these conditions
it was found that avermectin blocks
the motor neuron DEI response to indirect
stimulation but not direct stimulation. These
observations suggest that avermectins block
transmission between interneurons in the nerve
and the excitatory neurons. Avermectins have
more than one site of action, and these include
ion channels in both muscle membranes and
neuronal membranes. These observations are
consistent with the immunological identification
of GluCl subunits on the nerve cords
and motoneuron commissures of Haemonchus
contortus and Ascaris suum (Table 15.3). There
are also inhibitory glutamate receptors on the
muscle cells of the female reproductive tract of
Ascaris. Macrocyclic lactones have inhibitory
effects on egg laying and fertility. The effect
may account for much of the efficacy of ivermectin
treatment in controlling infections by
Onchocerca volvulus.
Cloning of GluCl subunits from parasitic
nematodes
Compared to C. elegans, we know less of the
molecular biology of the GluCls from parasitic
species. Our knowledge is summarized in
Table 15.3. Three GluCl genes have been identified
in H. contortus. Two of these are orthologous
to C. elegans glc-2 and avr-14, and the
pattern of alternative splicing of avr-14 is conserved
between the two species. Not only that,
but the expression of avr-14 on ring and cord
motoneurons appears similar in both C. elegans
and H. contortus. The GluCl3B subunit from
both species, but not the GluCl3A subunit,
is able to bind ivermectin when expressed
alone. Avr-14 is the gene found most widely in
parasitic nematodes, and is present in A. suum
and the filariae, O. volvulus and D. immitis,
though alternative splicing does not appear to
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