Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside.
The cyclooctadepsipeptide emodepside and its parent compound PF1022A are broad-spectrum nematicidal drugs which are able to eliminate nematodes resistant to other anthelmintics. The mode of action of cyclooctadepsipeptides is only partially understood, but involves the latrophilin Lat-1 receptor and...
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2014
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ftdoajarticles:oai:doaj.org/article:eee59e0458bc4c27a811a0d3f320d95e 2023-05-15T15:15:32+02:00 Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. Daniel Kulke Georg von Samson-Himmelstjerna Sandra M Miltsch Adrian J Wolstenholme Aaron R Jex Robin B Gasser Cristina Ballesteros Timothy G Geary Jennifer Keiser Simon Townson Achim Harder Jürgen Krücken 2014-12-01T00:00:00Z https://doi.org/10.1371/journal.pntd.0003401 https://doaj.org/article/eee59e0458bc4c27a811a0d3f320d95e EN eng Public Library of Science (PLoS) https://doi.org/10.1371/journal.pntd.0003401 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003401 https://doaj.org/article/eee59e0458bc4c27a811a0d3f320d95e PLoS Neglected Tropical Diseases, Vol 8, Iss 12, p e3401 (2014) Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 article 2014 ftdoajarticles https://doi.org/10.1371/journal.pntd.0003401 2022-12-31T07:51:24Z The cyclooctadepsipeptide emodepside and its parent compound PF1022A are broad-spectrum nematicidal drugs which are able to eliminate nematodes resistant to other anthelmintics. The mode of action of cyclooctadepsipeptides is only partially understood, but involves the latrophilin Lat-1 receptor and the voltage- and calcium-activated potassium channel Slo-1. Genetic evidence suggests that emodepside exerts its anthelmintic activity predominantly through Slo-1. Indeed, slo-1 deficient Caenorhabditis elegans strains are completely emodepside resistant. However, direct effects of emodepside on Slo-1 have not been reported and these channels have only been characterized for C. elegans and related Strongylida. Molecular and bioinformatic analyses identified full-length Slo-1 cDNAs of Ascaris suum, Parascaris equorum, Toxocara canis, Dirofilaria immitis, Brugia malayi, Onchocerca gutturosa and Strongyloides ratti. Two paralogs were identified in the trichocephalids Trichuris muris, Trichuris suis and Trichinella spiralis. Several splice variants encoding truncated channels were identified in Trichuris spp. Slo-1 channels of trichocephalids form a monophyletic group, showing that duplication occurred after the divergence of Enoplea and Chromadorea. To explore the function of a representative protein, C. elegans Slo-1a was expressed in Xenopus laevis oocytes and studied in electrophysiological (voltage-clamp) experiments. Incubation of oocytes with 1-10 µM emodepside caused significantly increased currents over a wide range of step potentials in the absence of experimentally increased intracellular Ca2+, suggesting that emodepside directly opens C. elegans Slo-1a. Emodepside wash-out did not reverse the effect and the Slo-1 inhibitor verruculogen was only effective when applied before, but not after, emodepside. The identification of several splice variants and paralogs in some parasitic nematodes suggests that there are substantial differences in channel properties among species. Most importantly, this study showed for ... Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic PLoS Neglected Tropical Diseases 8 12 e3401 |
institution |
Open Polar |
collection |
Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
spellingShingle |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 Daniel Kulke Georg von Samson-Himmelstjerna Sandra M Miltsch Adrian J Wolstenholme Aaron R Jex Robin B Gasser Cristina Ballesteros Timothy G Geary Jennifer Keiser Simon Townson Achim Harder Jürgen Krücken Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. |
topic_facet |
Arctic medicine. Tropical medicine RC955-962 Public aspects of medicine RA1-1270 |
description |
The cyclooctadepsipeptide emodepside and its parent compound PF1022A are broad-spectrum nematicidal drugs which are able to eliminate nematodes resistant to other anthelmintics. The mode of action of cyclooctadepsipeptides is only partially understood, but involves the latrophilin Lat-1 receptor and the voltage- and calcium-activated potassium channel Slo-1. Genetic evidence suggests that emodepside exerts its anthelmintic activity predominantly through Slo-1. Indeed, slo-1 deficient Caenorhabditis elegans strains are completely emodepside resistant. However, direct effects of emodepside on Slo-1 have not been reported and these channels have only been characterized for C. elegans and related Strongylida. Molecular and bioinformatic analyses identified full-length Slo-1 cDNAs of Ascaris suum, Parascaris equorum, Toxocara canis, Dirofilaria immitis, Brugia malayi, Onchocerca gutturosa and Strongyloides ratti. Two paralogs were identified in the trichocephalids Trichuris muris, Trichuris suis and Trichinella spiralis. Several splice variants encoding truncated channels were identified in Trichuris spp. Slo-1 channels of trichocephalids form a monophyletic group, showing that duplication occurred after the divergence of Enoplea and Chromadorea. To explore the function of a representative protein, C. elegans Slo-1a was expressed in Xenopus laevis oocytes and studied in electrophysiological (voltage-clamp) experiments. Incubation of oocytes with 1-10 µM emodepside caused significantly increased currents over a wide range of step potentials in the absence of experimentally increased intracellular Ca2+, suggesting that emodepside directly opens C. elegans Slo-1a. Emodepside wash-out did not reverse the effect and the Slo-1 inhibitor verruculogen was only effective when applied before, but not after, emodepside. The identification of several splice variants and paralogs in some parasitic nematodes suggests that there are substantial differences in channel properties among species. Most importantly, this study showed for ... |
format |
Article in Journal/Newspaper |
author |
Daniel Kulke Georg von Samson-Himmelstjerna Sandra M Miltsch Adrian J Wolstenholme Aaron R Jex Robin B Gasser Cristina Ballesteros Timothy G Geary Jennifer Keiser Simon Townson Achim Harder Jürgen Krücken |
author_facet |
Daniel Kulke Georg von Samson-Himmelstjerna Sandra M Miltsch Adrian J Wolstenholme Aaron R Jex Robin B Gasser Cristina Ballesteros Timothy G Geary Jennifer Keiser Simon Townson Achim Harder Jürgen Krücken |
author_sort |
Daniel Kulke |
title |
Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. |
title_short |
Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. |
title_full |
Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. |
title_fullStr |
Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. |
title_full_unstemmed |
Characterization of the Ca2+-gated and voltage-dependent K+-channel Slo-1 of nematodes and its interaction with emodepside. |
title_sort |
characterization of the ca2+-gated and voltage-dependent k+-channel slo-1 of nematodes and its interaction with emodepside. |
publisher |
Public Library of Science (PLoS) |
publishDate |
2014 |
url |
https://doi.org/10.1371/journal.pntd.0003401 https://doaj.org/article/eee59e0458bc4c27a811a0d3f320d95e |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
PLoS Neglected Tropical Diseases, Vol 8, Iss 12, p e3401 (2014) |
op_relation |
https://doi.org/10.1371/journal.pntd.0003401 https://doaj.org/toc/1935-2727 https://doaj.org/toc/1935-2735 1935-2727 1935-2735 doi:10.1371/journal.pntd.0003401 https://doaj.org/article/eee59e0458bc4c27a811a0d3f320d95e |
op_doi |
https://doi.org/10.1371/journal.pntd.0003401 |
container_title |
PLoS Neglected Tropical Diseases |
container_volume |
8 |
container_issue |
12 |
container_start_page |
e3401 |
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