trans

368 NEUROTRANSMITTERS
proteins required for docking and priming
include Munc13s, neurexins, SNAP-25 and
syntaxins, and proteins that are associated
with these proteins include complexins, Munc
18s, NSF, and //-SNAPs.
In C. elegans, unc-17 codes for an acetylcholine
transporter, and an unc-17 null mutant
is resistant to anti-cholinesterase. In a similar
way, mutations in unc-13 (which encodes
MUNC-13), unc-18 (which encodes MUNC-
18S), and syt-1 (which encodes synaptotagmin)
in C. elegans also give rise to anti-cholinesterase
resistance. The explanation for the resistance
and the partial paralysis of the nematode relates
to the impaired release of acetylcholine, which
reduces motility but makes the worm less sensitive
to the effects of cholinesterase antagonism.
Pharmacology of the acetylcholine receptor
Low concentrations of nicotine produce contractions
of Ascaris body muscle strips like
acetylcholine does. The acetylcholine-induced
contractions are blocked by tubocurarine but
not by atropine, so that the A. suum acetylcholine
receptors have some of the pharmacological
properties of vertebrate nicotinic
receptors. For example, the potent ganglionic
nicotinic agonist dimethylphenylpiperazinium
is more potent than acetylcholine in Ascaris,
and the potent ganglionic nicotinic antagonist
mecamylamine is the most potent acetylcholine
antagonist, more potent than tubocurarine.
In contrast, hexamethonium, a potent
ganglionic antagonist in vertebrates, had a
low potency in Ascaris. Therefore, the Ascaris
acetylcholine receptors cannot be classified as
either ganglionic or neuromuscular, and can
be regarded as a separate subtype of nicotinic
receptor.
Electrophysiological techniques have also
been used to examine effects of cholinergic
agonists and antagonists on muscle. Levamisole
and pyrantel are more potent agonists at the
Ascaris muscle acetylcholine receptor than at
vertebrate nicotinic receptors, where they have
only weak nicotinic actions. The selective action
of these drugs allows them to be used as effective
anthelmintics, killing the nematode parasite
but not the host. The degree of selectivity
will obviously affect the safety and efficacy
of any nicotinic drug selected for therapeutic
purposes.
Pilocarpine and muscarine cause a slight
hyperpolarization (up to 3 mV) rather than
a depolarization. These observations raise
the possibility that, in addition to the nicotiniclike
receptors, muscle cells may possess
muscarinic-like receptors for acetylcholine.
Janet Richmond has demonstrated, with electrophysiological
experiments on C. elegans,
the presence of two types of acetylcholinegated
ion-channel receptor on muscle. Firstly,
there is a non-desensitizing response to levamisole
which requires the presence of UNC-
28 and UNC-38 subunits; and secondly, a
rapidly desensitizing response to nicotine that
is blocked by dihydro--erythroidine. Thus
there are at least two types of ionotropic
acetylcholine receptor: a levamisole-preferring
receptor, and a nicotine-preferring, dihydro-
-erythroidine-blockable receptor. Interestingly,
the anthelmintic paraherquamide is a
more potent selective antagonist and will also
separate these two receptor types.
Cholinergic receptor anthelmintics
The anthelmintics that act as agonists to open
acetylcholine ion-channel receptors of nematodes
include the imidazothiazoles (levamisole
and butamisole), the tetrahydropyrimidines
(pyrantel, morantel and oxantel), the quaternary
ammonium salts (bephenium and thenium)
and the pyridines (methyridine).
Intracellular recording techniques on A. suum
muscle were used by Aubry to observe effects
of bath-applied tetramisole (a D, L racemic
BIOCHEMISTRY AND CELL BIOLOGY: HELMINTHS