trans

NEUROTRANSMITTERS IN NEMATODES 373
(domoate kainate glutamate aspartate)
that are similar to vertebrate kainate
receptors. In the DI motoneurons, glutamate
produces a hyperpolarization that may be
mediated via an intervening inhibitory neuron.
These observations suggest the presence
of excitatory glutamate receptors in nematodes,
and the cloning of the AMPA-like glutamate
receptor gene glr-1 from C. elegans
confirms their presence. Mutants of glr-1 are
sluggish and defective in mechanosensory
behavior. Electrogenic glutamate transporters
are also present in the hypodermis. This hypodermal
transporter may serve as a buffer, inactivating
glutamate synapses throughout the
nervous system in parallel to the hypodermal
cholinesterase.
FIGURE 15.14 GABA- and piperazine-activated
single-channel currents. The open times of the GABAactivated
channels are longer on average (mean open
time 32 ms) than the piperazine-activated channels
(18 ms). Piperazine also requires a higher concentration
to produce a similar opening rate to GABA, and so
is less potent than GABA.
Glutamate
Excitatory effects
A number of anthelmintics, including kainate,
have a chemical structure similar to the excitatory
amino acid glutamate. Kainate, domoic
acid and quisqualate have been used as
anthelmintics in Asia for a long time, and are
now usually used to study vertebrate glutamate
receptors. DE2 motorneurons of Ascaris
show depolarizing potentials and conductance
changes in response to glutamate agonists
Inhibitory effects: the search for the
ivermectin receptor
The success of ivermectin (Merck) as an
anthelmintic, and its very potent effects against
nematodes, led to a search for the mode of
action of these compounds. One of the initial
helpful observations was that ivermectin was
found to bind specifically to membrane preparations
of C. elegans. The lipophilic nature of
the avermectins made detection of specific
binding to receptors, present in low number,
very difficult.
C. elegans was an excellent model for these
mode-of-action studies because large numbers
of worms could be grown in fermentation
tanks to produce substantial amounts of RNA
for extraction and expression. The nematode
GluCl ion channels were first recognized by
expression of a glutamate-activated chloride
current, sensitive to avermectins, in Xenopus
oocytes injected with C. elegans RNA. Expression
cloning then led to the recognition of
two C. elegans channel subunits, GluCl1 on
chromosome V and GluCl on chromosome I.
The GluCl subunit is responsible for the
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