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378 NEUROTRANSMITTERS
crossed the cuticle, it is then able to interact
with the GluCl receptors. At least three different
GluCl subunits have been identified that
form inhibitory ion channels on muscles of
the pharynx, motor neurons and other neurons,
and in addition perhaps on the female
reproductive tract. Neurons that possess the
GluCl channels connect via gap junctions that
are made up of innexins, coded for by unc-7
and unc-9 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,
an effect mediated across gap junctions
(unc-7 and unc-9) to the pharynx. Ivermectin
removal may be influenced by p-glycoprotein
excretion and is perhaps located on intestinal
epithelial cells. The mode of action and genetics
of resistance in C. elegans implies that the
development of resistance in parasitic nematodes
requires the simultaneous mutation of
several genes to develop a high level of resistance.
For example, factors that increase the
concentration of macrocyclic lactones, or factors
that increase the electrical effects of stimulation
of the GluCl ion channel, such as unc 7
or unc 9, will increase susceptibility. However,
some studies suggest that ivermectin resistance
in parasitic nematodes is simpler and may in
fact be dominant.
5-HT
The majority of studies on nematode neuromuscular
systems have focused on the body
wall and nerve cord, but the pharyngeal
muscle is also important for the survival of
most nematodes. Pharyngeal pumping is necessary
for feeding; in fact nematodes spend a
large part of their time searching for food and
feeding. Pumping is regulated by a range
of neurotransmitters, including acetycholine,
glutamate, GABA, 5-HT, dopamine and a range
of neuropeptides (including KSAYMRFamide).
In C. elegans 5-HT stimulates and dopamine
depresses pharyngeal pumping. 5-HT also
modulates pharyngeal pumping in A. suum
and modulates activity of the vagina vera. The
injection of 5-HT into Ascaris causes a rapid
paralysis in animals that were moving. It causes
depolarization of the male-specific transverse
ventral muscle and curling in the male, mimicking
mating behavior. It also abolishes slow
potentials in VI motor neurons of Ascaris. 5-
HT is localized in Ascaris in a pair of neurons
in the pharynx of both sexes, and in five cells
in the ventral cord of the male tail. The pharyngeal
cells are probably neurosecretary cells
and homologous to the C. elegans neurosecretary
motor neurons (NSM).
A 5-HT receptor isoform that appears to
be alternatively spliced has been identified in
A. suum. AS1–3 are expressed in the pharynx,
and AS1 and AS2 are expressed in the body
wall muscle. Thus 5-HT has an inhibitory/
modulatory effect on most body muscle and
stimulates pharyngeal pumping.
FMRFamide-related peptides
Short peptides referred to as FMRFamides may
act in nematodes as co-transmitters along with
the transmitters mentioned above.
A tetrapeptide FMRFamide was first isolated
from the mollusc Macrocallista nimbosa.
FMRFamide, short for Phe-Met-Arg-PheNH 2 , is
cardioexcitatory in M. nimbosa and is neuroactive
in other invertebrates. FMRFamide-
Related Peptides, or FaRPs, have been identified
in species other than molluscs. Immunoreactivity
to FMRFamide is present in rats, chickens,
cattle, frogs and teleost fish, in addition to
numerous invertebrates. Since the discovery
of the original FaRP, FMRFamide, FaRPs have
become recognized as an important group
of neuroactive peptides, particularly amongst
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