Resistance to levamisole resolved at the single‐channel level

Robertson, Alan P.; Bjørn, H.; Martin, Richard J.

doi:10.1096/fasebj.13.6.749

Cited by 91 publications

(107 citation statements)

References 34 publications

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“…As judged by the single-component amplitude histogram and the homogeneous kinetics, it is highly probable that C. elegans at L1 stage contain a single, or at least one highly predominant, L-AChR subtype. Although no unitary currents have been described before for C. elegans nAChRs, few reports have shown AChR channels from nematode parasites (Pennington and Martin, 1990;Robertson and Martin, 1993;Robertson et al, 1999;Levandoski et al, 2005). The comparison of channel properties of L-AChRs between parasites and C. elegans reveals that they have similar conductances and mean open times (Levandoski et al, 2005).…”

Section: Discussionmentioning

confidence: 96%

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: Discussionmentioning

confidence: 96%

Activation of Single Nicotinic Receptor Channels fromCaenorhabditis elegansMuscle

Rayes¹,

Flamini²,

Hernando³

et al. 2007

Mol Pharmacol

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“…In contrast, expression of ACR-16, which is 47% identical to chicken ␣8, in Xenopus oocytes, produces channels sensitive to acetylcholine but insensitive to levamisole or pyrantel (Ballivet et al, 1996). In the intact nematode, levamisole pyrantel, morantel, and oxantel activate nAChRs on Ascaris muscle (Martin et al, 1996), and single channel recordings of nAChRs in Oesophogostomum dentatum reveal the presence of four subtypes on somatic muscle (Robertson et al, 1999). There is therefore evidence for the presence of multiple subtypes of nAChR in nematodes with ligands that can be selective for different subtypes of receptor.…”

Section: Discussionmentioning

confidence: 97%

“…Levamisole and pyrantel are potent anthelmintics that act as selective agonists on nematode nAChRs (Martin et al, 1996). Nematode nAChRs, like vertebrate neuronal nAChRs, are taken to be composed of a pentamer of subunits, and a number of different subtypes are present on muscle (Robertson et al, 1999;Richmond and Jorgensen, 1999). The distinctive pharmacology of some nematode nAChRs seems to relate to the distinctive molecular structure of the agonist binding site formed by part of the ␣-subunit .…”

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confidence: 99%

Paraherquamide and 2-Deoxy-paraherquamide Distinguish Cholinergic Receptor Subtypes in Ascaris Muscle

Robertson¹,

Clark²,

Burns³

et al. 2002

J Pharmacol Exp Ther

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114

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Paraherquamide is a novel natural anthelmintic product with a mode of action that is incompletely characterized. Nicotine and cholinergic-anthelmintic agonists of different chemical classes were used to produce contraction in Ascaris muscle strips. Paraherquamide and a semisynthetic derivative, 2-deoxy-paraherquamide, antagonized these responses. Analysis of the actions of the antagonists was made using the simple competitive model and nonlinear regression to estimate the pK B values of the antagonists. The analysis was tested using Clark plots. The pK B values for paraherquamide were: nicotine, 5.86 Ϯ 0.14; levamisole, 6.61 Ϯ 0.19; pyrantel, 6.50 Ϯ 0.11; and bephenium, 6.75 Ϯ 0.15. The pK B of nicotine was significantly different from the pK B values for levamisole, pyrantel, and bephenium, showing that paraherquamide can distinguish a subtype of cholinergic receptors sensitive to nicotine and a subtype of cholinergic receptors sensitive to levamisole, pyrantel, and bephenium. The pK B values for 2-deoxy-paraherquamide were: levamisole, 5.31 Ϯ 0.13; pyrantel, 5.63 Ϯ 0.10; and bephenium, 6.07 Ϯ 0.13. The Clark plots of the antagonism illustrated the degree of fit to the competitive model for 2-deoxy-paraherquamide. 2-Deoxy-paraherquamide selectively antagonized the effects of bephenium; the pK B values of levamisole and pyrantel were significantly different from the pK B of bephenium. Paraherquamide and 2-deoxy-paraherquamide are selective competitive cholinergic antagonists that distinguish subtypes of cholinergic receptor in Ascaris muscle corresponding to nicotine-, levamisole-, and bephenium-sensitive receptors.Nematode parasite infections of humans and animals cause disease with loss of productivity, debility, and occasionally death. Ascariasis and hookworm infections are carried by 1.6 billion people throughout the world and in 2% of cases cause loss of life. The use of therapeutic compounds forms a major component of control, and the development of novel therapeutic agents is required to deal with the increasing levels of resistance to existing drugs.Paraherquamide (Fig. 1) is a novel anthelmintic (Yamazaki et al., 1981) that is an alkaloid fermentation product originally isolated from Penicillium paraherquii. The anthelmintic property of paraherquamide was first identified using jirds infected with Trichostrongylus colubriformis (Ostlind et al., 1990). Paraherquamide produces paralysis of parasitic nematodes in culture, without an effect on ATP, suggesting that it does not act as a metabolic poison (Thompson et al., 1996). Interestingly, one of the toxic effects of paraherquamide in the dog (Shoop et al., 1990) is a prolapsed nictitating membrane, an effect that suggests antagonism of neuronal nicotinic receptors (nAChRs). Recently, it has been reported (E.

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“…The inverse relationship between the two drugs in the present study indicates that resistance to pyrantel may involve a reduction in pyrantel-sensitive receptors in the resistant isolate, alongside a compensatory increase in bephenium-sensitive nAchR subtypes, in order to maintain a net nAchR population of sufficient quantity to permit normal transmission in the neuromuscular system. Changes in the relative levels of different receptor subtypes have been demonstrated in high-resolution electrophysiological studies with susceptible and resistant Oesophagostomum dentatum worms by Robertson et al (22).…”

Section: Discussionmentioning

confidence: 90%

Phenotypic Characterization of Two Ancylostoma caninum Isolates with Different Susceptibilities to the Anthelmintic Pyrantel

Kopp

Coleman

McCarthy

et al. 2008

Antimicrob Agents Chemother

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The anthelmintic pyrantel plays an important role in the control of gastrointestinal helminths of humans and domestic animals. Despite the demonstration of pyrantel resistance in several helminth species over the last 20 years, the resistance mechanism remains unclear. It has been hypothesized that resistance may arise as a consequence of changes to the relative proportions of subpopulations of nicotinic acetylcholine receptors (nAchRs). To test this hypothesis, we examined the responses of two isolates of the canine hookworm Ancylostoma caninum with low-level resistance (isolate NT) and high-level resistance (isolate PR) to pyrantel to nicotinic agonist drugs reported to be selective for three nAchR subtypes. We used larval motility and conformation assays and force transduction experiments with adult worms. Pyrantel and levamisole were less potent against larvae of isolate PR than larvae of isolate NT (up to an 18-fold increase in the 50% inhibitory concentration); on the other hand, bephenium was more potent against larvae of isolate PR than larvae of isolate NT (twofold) and nicotine had the same potency against larvae of both isolates. In adults, pyrantel, levamisole, and nicotine were less potent against isolate PR than isolate NT (two-to threefold), but the potency of bephenium against the two isolates was equivalent. Our data indicate a complex pattern of nAchRs in this species and suggest that the two isolates differ in their relative sensitivities to agonists targeting different nAchRs.

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Resistance to levamisole resolved at the single‐channel level

Cited by 91 publications

References 34 publications

Activation of Single Nicotinic Receptor Channels fromCaenorhabditis elegansMuscle

Activation of Single Nicotinic Receptor Channels fromCaenorhabditis elegansMuscle

Paraherquamide and 2-Deoxy-paraherquamide Distinguish Cholinergic Receptor Subtypes in Ascaris Muscle

Phenotypic Characterization of Two Ancylostoma caninum Isolates with Different Susceptibilities to the Anthelmintic Pyrantel

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