Activation and cooperative multi‐ion block of single nicotinic‐acetylcholine channel currents of <i>Ascaris</i> muscle by the tetrahydropyrimidine anthelmintic, morantel

Evans, A. Mark; Martin, Richard J.

doi:10.1111/j.1476-5381.1996.tb15515.x

Cited by 35 publications

(36 citation statements)

References 43 publications

(57 reference statements)

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“…The duration of the briefest closed component and its relative area remain constant between 0.5 and 10 M ACh (p Ͼ 0.05) ( Table 1). This component may represent brief closures during single activation, as described before for vertebrate and Ascaris suum nAChRs (Colquhoun and Sakmann, 1985;Evans and Martin, 1996). At higher ACh concentrations, closed-time distributions show an increase in the area of the briefest closed component, caused by the concentration-dependent increase of brief closures corresponding to blocked periods (0.10 Ϯ 0.04 and 0.45 Ϯ 0.01 at 10 and 300 M ACh, respectively; p Ͻ 0.05).…”

Section: Resultsmentioning

confidence: 53%

“…In contrast, neither flickering nor closed components associated to blocked periods are observed in the presence of anthelmintics, suggesting that the drugs dissociate from the channel very slowly. Alternatively, their blocking mechanisms may deviate from the simple open-channel block model, as reported for morantel in A. suum nAChR (Evans and Martin, 1996).…”

Section: Discussionmentioning

confidence: 96%

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Activation of Single Nicotinic Receptor Channels fromCaenorhabditis elegansMuscle

Rayes¹,

Flamini²,

Hernando³

et al. 2007

Mol Pharmacol

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Nicotinic acetylcholine receptors (nAChRs) are pentameric neurotransmitter-gated ion channels that mediate synaptic transmission throughout the nervous system in vertebrates and invertebrates. Caenorhabditis elegans is a nonmammalian model for the study of the nervous system and a model of parasitic nematodes. Nematode muscle nAChRs are of considerable interest because they are targets for anthelmintic drugs. We show single-channel activity of C. elegans muscle nAChRs for the first time. Our results reveal that in the L1 larval stage acetylcholine (ACh) activates mainly a levamisole-sensitive nAChR (L-AChR). A single population of 39 pS channels, which are 5-fold more sensitive to levamisole than ACh, is detected. In contrast to mammalian nAChRs, open durations are longer for levamisole than for ACh. Studies in mutant strains reveal that UNC-38, UNC-63, and UNC-29 subunits are assembled into a single L-AChR in the L1 stage and that these subunits are irreplaceable, suggesting that they are vital for receptor function throughout development. Recordings from a strain mutated in the LEV-1 subunit show a main population of channels with lower conductance (26 pS), prolonged open durations, and reduced sensitivity to levamisole. Thus, although LEV-1 is preferentially incorporated into native L-AChRs, receptors lacking this subunit can still function. No single-channel activity from levamisole-insensitive nAChRs is detected. Thus, during neuromuscular transmission in C. elegans, the majority of AChactivated current flows through L-AChRs. This study contributes to the understanding of the molecular mechanisms underlying functional diversity of the nAChR family and offers an excellent strategy to test novel antiparasitic drugs.

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Section: Resultsmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 96%

Activation of Single Nicotinic Receptor Channels fromCaenorhabditis elegansMuscle

Rayes¹,

Flamini²,

Hernando³

et al. 2007

Mol Pharmacol

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“…Levamisole belongs to the ionotropic cholinergic agonist group of anthelmintics that includes pyrantel, and that selectively produces muscle cell depolarization and spastic paralysis in parasitic nematodes (Aceves et al, 1970;Aubry et al, 1970). We have shown, using current-clamp, voltage-clamp and patch-clamp, that electrophysiological responses to these anthelmintics can be observed in body muscle cells of the nematode parasites Ascaris suum and Oesophagostomum dentatum (Martin, 1982;Pennington and Martin, 1990;Robertson and Martin, 1993;Robertson et al, 1994Robertson et al, , 2002Dale and Martin, 1995;Evans and Martin, 1996;Martin et al, 2002;Trailovic et al, 2002). These studies have identified nematode nicotinic acetylcholine gated receptor channels (nAChRs) over the nematode muscle cell surface that is selectively and directly gated by these anthelmintics.…”

Section: Introductionmentioning

confidence: 99%

Effects of the muscarinic agonist, 5-methylfurmethiodide, on contraction and electrophysiology of Ascaris suum muscle

Trailovic

Verma

Clark

et al. 2008

International Journal for Parasitology

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Contraction and electrophysiological effects of 5-methylfurmethiodide (MFI), a selective muscarinic agonist in mammals, were tested on Ascaris suum muscle strips. In a contraction assay, MFI produced weak contraction and was less potent than levamisole and acetylcholine. Atropine (3 µM) a nonselective muscarinic antagonist in mammalian preparations, did not affect contractions produced by MFI. Mecamylamine (3 µM) a nicotinic antagonist in A. suum preparations, blocked the MFI contractions indicating that MFI had weak nicotinic agonist actions. In two-micropipette currentclamp experiments MFI, at concentrations greater than 10 µM, produced concentration-dependent depolarizations and small increases in membrane conductance. The depolarizing effects were not abolished by perfusing the preparation in a calcium-free Ascaris Ringer solution to block synaptic transmission, suggesting that MFI effects were mediated by receptors on the muscle and were calcium-independent. A high concentration of mecamylamine, 30 µM, only reduced the depolarizing responses by 42%, indicating that MFI also had effects on non-nicotinic receptors. Three nonnicotinic effects in the presence of 30 µM mecamylamine were identified using voltage-clamp techniques: i) MFI produced opening of mecamylamine-resistant non-selective-cation channel currents; ii) MFI inhibited opening of voltage-activated potassium currents; and iii) MFI increased the threshold of voltage-activated calcium currents. We suggest that a drug that is more selective for voltage-activated potassium currents, without effects on other channels like MIF, may be exploited pharmacologically as a novel anthelmintic or as an agent to potentiate the action of levamisole. In a larval migration assay we demonstrated that 4-aminopyridine (4-AP: a potassium channel blocker) potentiated the effects of levamisole but MFI did not.

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“…These drugs act upon the nicotinic acetylcholine receptors (nAChR) on the surface of somatic muscle cells in nematodes, leading to depolarization and spastic paralysis that facilitates parasite expulsion (Unwin, 1995;Evans and Martin, 1996). The laboratory-produced LEV resistant Caenorhabditis elegans worms showed that a large number of genes are involved in the observed resistance.…”

Section: Specific Mechanisms Of Anthelmintic Resistancementioning

confidence: 99%

“…The imidothiazole group including LEV mimics the action of acetylcholine. These drugs act upon the nicotinic acetylcholine receptors (nAChR) on the surface of somatic muscle cells in nematodes, leading to depolarization and spastic paralysis that facilitates parasite expulsion (Unwin, 1995;Evans and Martin, 1996). Macrocyclic lactones (avermectins and milbemycins) cause flaccid paralysis of the somatic musculature in the parasite body, thus disrupting food ingestion by inhibiting the pharyngeal pump (Kotze, 1998;Sangster and Gill, 1999;Rana and Misra-Bhattacharya, 2013).…”

Section: Control Of Parasitic Nematodesmentioning

confidence: 99%

The role of drug efflux systems in anthelmintic resistance in parasitic nematodes

Raza¹

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Activation and cooperative multi‐ion block of single nicotinic‐acetylcholine channel currents of Ascaris muscle by the tetrahydropyrimidine anthelmintic, morantel

Cited by 35 publications

References 43 publications

Activation of Single Nicotinic Receptor Channels fromCaenorhabditis elegansMuscle

Activation of Single Nicotinic Receptor Channels fromCaenorhabditis elegansMuscle

Effects of the muscarinic agonist, 5-methylfurmethiodide, on contraction and electrophysiology of Ascaris suum muscle

The role of drug efflux systems in anthelmintic resistance in parasitic nematodes

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