Latrophilin‐like receptor from the parasitic nematode<i>Haemonchus contortus</i>as target for the anthelmintic depsipeptide PF1022A

Saeger, Beate; Schmitt-Wrede, Hans-Peter; Dehnhardt, Markus; Benten, W. Peter M.; Krücken, Jürgen; Harder, Achim; Samson‐Himmelstjerna, Georg von; Wiegand, Herbert; Wunderlich, Frank

doi:10.1096/fj.00-0664fje

Cited by 83 publications

(65 citation statements)

References 40 publications

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“…Heterologous Expression of Human BK Channel in C. elegans molecular mechanisms of action. Two modes of action have been demonstrated: an emodepside receptor with homology to mammalian latrophilin G protein-coupled receptors has been expression-cloned from Haemonchus contortus (Saeger et al, 2001), and its C. elegans ortholog, LAT-1, confers sensitivity of the pharyngeal system to emodepside (Willson et al, 2004). However, C. elegans latrophilin mutants remain susceptible to the inhibitory effects of emodepside on locomotion , indicating that another effector must also be involved.…”

Section: Discussionmentioning

confidence: 99%

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

Crisford¹,

Murray²,

O’Connor³

et al. 2011

Mol Pharmacol

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Emodepside is a resistance-breaking anthelmintic of a new chemical class, the cyclooctadepsipeptides. A major determinant of its anthelmintic effect is the calcium-activated potassium channel SLO-1. SLO-1 belongs to a family of channels that are highly conserved across the animal phyla and regulate neurosecretion, hormone release, muscle contraction, and neuronal network excitability. To investigate the selective toxicity of emodepside, we performed transgenic experiments in which the nematode SLO-1 channel was swapped for a mammalian ortholog, human KCNMA1. Expression of either the human channel or Caenorhabditis elegans slo-1 from the native slo-1 promoter in a C. elegans slo-1 functional null mutant rescued behavioral deficits that otherwise resulted from loss of slo-1 signaling. However, worms expressing the human channel were 10-to 100-fold less sensitive to emodepside than those expressing the nematode channel. Strains expressing the human KCNMA1 channel were preferentially sensitive to the mammalian channel agonists NS1619 and rottlerin. In the C. elegans pharyngeal nervous system, slo-1 is expressed in neurons, not muscle, and cell-specific rescue experiments have previously shown that emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signaling in the nervous system. Here we show that ectopic overexpression of slo-1 in pharyngeal muscle confers sensitivity of the muscle to emodepside, consistent with a direct interaction of emodepside with the channel. Taken together, these data predict an emodepside-selective pharmacophore harbored by SLO-1. This has implications for the development of this drug/ target interface for the treatment of helminth infections.

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Section: Discussionmentioning

confidence: 99%

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

Crisford¹,

Murray²,

O’Connor³

et al. 2011

Mol Pharmacol

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“…Computer Analysis-The pHCl clones were sequenced using the LI-COR 4200 laser fluorescent sequencing system (MWG Biotech, Ebersberg, Germany), Fluorescence Labeled Cycle Sequencing Kit (Amersham Biosciences), and infrared fluorescence-labeled primers (MWG) as described before (11). The sequences were analyzed with SAPS (12), ScanPROSITE, Prot-Param, and Predict Protein (13).…”

Section: Methodsmentioning

confidence: 99%

A Novel Chloride Channel in Drosophila melanogaster Is Inhibited by Protons

Schnizler

Saeger

Pfeffer

et al. 2005

Journal of Biological Chemistry

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A systematic analysis of the Drosophila genome data reveals the existence of pHCl, a novel member of ligand-gated ion channel subunits. pHCl shows nearly identical similarity to glutamate-, glycine-, and histamine-gated ion channels, does however not belong to any of these ion channel types. We identified three different sites, where splicing generates multiple transcripts of the pHCl mRNA. The pHCl is expressed in Drosophila embryo, larvae, pupae, and the adult fly. In embryos, in situ hybridization detected pHCl in the neural cord and the hindgut. Functional expression of the three different splice variants of pHCl in oocytes of Xenopus laevis and Sf9 cells induces a chloride current with a linear current-voltage relationship that is inhibited by extracellular protons and activated by avermectins in a pH-dependent manner. Further, currents through pHCl channels were induced by a raise in temperature. Our data give genetic and electrophysiological evidence that pHCl is a member of a new branch of ligand-gated ion channels in invertebrates with, however, a hitherto unique combination of pharmacological and biophysical properties.Ligand-gated ion channels (LGICs) 1 mediate the fast inhibitory and excitatory responses of neuronal and muscle cells to neurotransmitters. A universal feature of the type of "Cys-loop" class of LGIC is a common topology of four membrane-spanning segments (M1-M4) and a huge N-terminal extracellular domain with a hyperconservated cysteinebridge motive (1). In vertebrates this "Cys-bridge" family of phylogenetically related genes codes for cation channels activated by acetylcholine and serotonin or for anion channels activated by GABA and glycine (1). In addition, glutamateand serotonin-gated anion channel genes are known in invertebrates (2, 3). Recently, genes for histamine-gated chloride channels and GABA-gated cation channels were identified in invertebrates (4 -7). The molecular basis of further channel types like acetylcholine-gated chloride channels in invertebrates is, however, still unknown (8). Information from the Drosophila melanogaster genome sequencing project allows identifying all members of the superfamily of ligand-gated ion channels occurring in this species by bioinformatic analysis of new homologous genes. The summarized data obtained from several published bioinformatic analyses (5,6,9,10) show that the group of ligand-gated "chloride" channels consists of 12 genes that are coding for GABA, histamine, and glutamate receptors or new, homologous ion channel types. Four members of this group cannot be directly assigned to the GABA, glutamate, or histamine branches and thus code for putative new types of ligand-gated chloride channels with yet unknown function. In a systematic expression approach of these predicted novel types of ion channels in Xenopus oocytes, it was found that none of the typical neurotransmitters activated these novel types of channels (6). Therefore, we extended the molecular biological analysis of the mRNA and found that the gene CG6112 encodes fo...

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“…Predominant among these candidates is the phylogenetically conserved latrophilin receptor. Latrophilin was identified as a candidate receptor for cyclo-octadepsipeptides by expression cloning from Haemonchus contortus (Saeger et al 2001). It is a Class B G-protein-coupled receptor, so-called, because it binds the black widow spider toxin, latrotoxin (Lelianova et al 1997).…”

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Some Results on Mean Square Error for Factor Score Prediction

Krijnen¹

2006

Psychometrika

318

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The cyclo-octapdepsipeptide anthelmintic emodepside exerts a profound paralysis on parasitic and free-living nematodes. The neuromuscular junction is a significant determinant of this effect. Pharmacological and electrophysiological analyses in the parasitic nematode Ascaris suum have resolved that emodepside elicits a hyperpolarisation of body wall muscle, which is dependent on extracellular calcium and the efflux of potassium ions. The molecular basis for emodepside's action has been investigated in forward genetic screens in the free-living nematode Caenorhabditis elegans. Two screens for emodepside resistance, totalling 20,000 genomes, identified several mutants of slo-1, which encodes a calcium-activated potassium channel homologous to mammalian BK channels. Slo-1 null mutants are more than 1000-fold less sensitive to emodepside than wild-type C. elegans and tissue-specific expression studies show emodepside acts on SLO-1 in neurons regulating feeding and motility as well as acting on SLO-1 in body wall muscle. These genetic data, combined with physiological measurements in C. elegans and the earlier physiological analyses on A. suum, define a pivotal role for SLO-1 in the mode of action of emodepside. Additional signalling pathways have emerged as determinants of emodepside's mode of action through biochemical and hypothesis-driven approaches. Mutant analyses of these pathways suggest a modulatory role for each of them in emodepside's mode of action; however, they impart much more modest changes in the sensitivity to emodepside than mutations in slo-1. Taken together these studies identify SLO-1 as the major determinant of emodepside's anthelmintic activity. Structural information on the BK channels has advanced significantly in the last 2 years. Therefore, we rationalise this possibility by suggesting a model that speculates on the nature of the emodepside pharmacophore within the calcium-activated potassium channels.Keywords Cyclo-octadepsipeptide Á C. elegans Á Ascaris suum Á Anthelmintic Á BK channel Receptors and effectors for emodepsideEmodepside is a semi-synthetic derivative of the cyclooctadepsipeptide PF1022A, a secondary metabolite of the fungus Rosellinia spp. PF1022. It is effective against a wide-range of parasitic nematodes and has anthelminticresistance breaking properties suggesting a novel mode of action, for review see (Krucken et al. 2012). A key aspect of its efficacy is its ability to interfere with neuromuscular transmission in parasitic nematodes, an effect that was shown to be both calcium-and potassium dependent . It also inhibits neuromuscular function in the free-living nematode C. elegans, disrupting feeding, egg-laying and motility ). The inhibition of motility leads to complete paralysis and is consistent with dysfunction at the neuromuscular junction. Observation of the flaccid paralysis triggered by

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Latrophilin‐like receptor from the parasitic nematodeHaemonchus contortusas target for the anthelmintic depsipeptide PF1022A

Cited by 83 publications

References 40 publications

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

Selective Toxicity of the Anthelmintic Emodepside Revealed by Heterologous Expression of Human KCNMA1 inCaenorhabditis elegans

A Novel Chloride Channel in Drosophila melanogaster Is Inhibited by Protons

Some Results on Mean Square Error for Factor Score Prediction

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