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NEMATODES 333
pharynx at the end of each action potential. This
channel is biophysically similar to the HERG K
channel that repolarizes human heart muscle
cells following contraction, though these two
proteins are not highly related structurally.
Several mutations in exp-6 are lethal, suggesting
a critical role. Pharyngeal function in C. elegans
is also dependent on a K–Cl cotransporter,
KO2, that is expressed in pharyngeal muscle
membranes and is essential for survival under
hyperosmotic conditions. Other K channels
have been implicated in more posterior regions
of the intestine. The M-type K channels, kqt-1,
kqt-2 and kqt-3, are expressed in the proximal
and distal regions of the intestine. When
expressed in Xenopus oocytes they exhibit slow
activation kinetics resembling KCNQ-related
M-type K channels in vertebrate epithelial and
cardiac cells. Suppression of kqt-2 or kqt-3 leads
to prolongation of the defecation cycle. Though
the mechanism underlying this response has
not been determined, indirect evidence suggests
that these channels regulate the timing of
cytoplasmic Ca 2 oscillations in intestinal cells.
Many channels that regulate ion flux across
the pharynx are under control of the nervous
system. The rate of pharyngeal pumping in
nematodes is controlled, in part, by cholinergic
(MC in C. elegans), serotonergic (M3), glutamatergic
(M1 and M4) and neuropeptidergic
neurons, all of which innervate the pharynx. In
some cases, receptors for these transmitters
couple directly to ion channels, the biophysical
and molecular characteristics of which
are currently being delineated. In the case of
the peptidergic inputs, the G-protein-coupled
receptors and second messenger systems to
which they couple have not been identified.
Excretion
That the intestine participates in excretion is
supported by studies showing that each organic
acid present in PCF is also present in the lumen
of the intestine in adult A. suum. There is no
evidence for a concentrating effect as digesta
move into the caudal regions. However, indirect
evidence that questions the importance of
the intestine for organic acid excretion comes
from studies on adult A. suum. Neither the rate
of organic acid excretion into the medium nor
worm viability, based on ATP and motility levels,
is affected by ligation of the pharynx. Similarly,
chemical ligation of adult H. contortus
with ivermectin, which paralyzes the pharynx
and inhibits flow of digesta along the intestine,
does not affect the rates of excretion of propionic
or lactic acids, or worm viability. These
and related studies suggest that the cuticle–
hypodermis complex may be a more important
site than the intestine for excretion of
some metabolic end-products.
Role for intestinal P-glycoproteins in drug
elimination
The accumulation of some molecules by nematodes
may be affected by drug transporting
proteins, referred to as P-glycoproteins (pgps).
Pgps actively ‘pump’ drugs out of some cells,
thereby limiting exposure of the organism to
their therapeutic actions. In vertebrates, overexpression
of pgps has been linked to resistance
to some anti-cancer drugs, though their
relevance to this condition in the clinic remains
controversial. Ivermectin is a substrate for pgpmediated
extrusion from murine kidney epithelial
cells in vitro. Mice deficient in mdr1a, a
pgp-encoding gene, are susceptible to the toxic
actions of ivermectin, which accumulates in
the brains of these mutants to levels over 100-
fold greater than in wild-type mice. In C. elegans,
pgps are expressed primarily on apical
membranes of cells that form the intestine and
tubular system, a pattern consistent with a role
for these proteins (and internal surfaces) in
protecting the organism from toxic xenobiotics.
There are no reports describing pgp expression
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS