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Selective toxicity of the anthelmintic emodepside revealed by heterologous expression of human KCNMA1 in caenorhabditis elegans

Selective toxicity of the anthelmintic emodepside revealed by heterologous expression of human KCNMA1 in caenorhabditis elegans
Selective toxicity of the anthelmintic emodepside revealed by heterologous expression of human KCNMA1 in caenorhabditis elegans
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 orthologue, human KCNMA1. Expression of either the human channel or C. elegans slo-1 from the native slo-1 promoter in a C. elegans slo- functional null rescued behavioural deficits that otherwise resulted from loss of slo-1 signalling. 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 neurones not muscle and cell specific rescue experiments have previously shown that emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signalling in the nervous system. Here we show that ectopic over-expression 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 harboured by SLO-1. This has implications for the development of this drug/target interface for the treatment of helminth infections
0026-895X
1031-1043
Crisford, Anna
135675e1-a172-4d93-989b-93d1efb022c3
Murray, Caitriona
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O'Connor, Vincent
b005270b-0ec5-4429-874e-2f08c43cf86d
Edwards, Richard J.
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Kruger, Nina
80749c8a-3938-446c-a3fa-3e35d1b563ba
Welz, Claudia
7effdf23-c045-44b8-aa37-f423050d292e
von Samson-Himmelstjerna, Georg
e817b0f2-5c03-47a9-b046-a04b3dacfcf3
Harder, Achim
6bcbaba4-2209-45eb-a29f-5f1ac4476fa2
Walker, Robert J.
9368ac2d-f1e9-4bd9-a4b4-4a161c4aa140
Holden-Dye, Lindy
8032bf60-5db6-40cb-b71c-ddda9d212c8e
Crisford, Anna
135675e1-a172-4d93-989b-93d1efb022c3
Murray, Caitriona
6fcb874d-75d7-49aa-9219-8f9723d862fe
O'Connor, Vincent
b005270b-0ec5-4429-874e-2f08c43cf86d
Edwards, Richard J.
9d25e74f-dc0d-455a-832c-5f363d864c43
Kruger, Nina
80749c8a-3938-446c-a3fa-3e35d1b563ba
Welz, Claudia
7effdf23-c045-44b8-aa37-f423050d292e
von Samson-Himmelstjerna, Georg
e817b0f2-5c03-47a9-b046-a04b3dacfcf3
Harder, Achim
6bcbaba4-2209-45eb-a29f-5f1ac4476fa2
Walker, Robert J.
9368ac2d-f1e9-4bd9-a4b4-4a161c4aa140
Holden-Dye, Lindy
8032bf60-5db6-40cb-b71c-ddda9d212c8e

Crisford, Anna, Murray, Caitriona, O'Connor, Vincent, Edwards, Richard J., Kruger, Nina, Welz, Claudia, von Samson-Himmelstjerna, Georg, Harder, Achim, Walker, Robert J. and Holden-Dye, Lindy (2011) Selective toxicity of the anthelmintic emodepside revealed by heterologous expression of human KCNMA1 in caenorhabditis elegans. Molecular Pharmacology, 79 (6), 1031-1043. (doi:10.1124/mol.111.071043). (PMID:21415309)

Record type: Article

Abstract

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 orthologue, human KCNMA1. Expression of either the human channel or C. elegans slo-1 from the native slo-1 promoter in a C. elegans slo- functional null rescued behavioural deficits that otherwise resulted from loss of slo-1 signalling. 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 neurones not muscle and cell specific rescue experiments have previously shown that emodepside inhibits serotonin-stimulated feeding by interfering with SLO-1 signalling in the nervous system. Here we show that ectopic over-expression 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 harboured by SLO-1. This has implications for the development of this drug/target interface for the treatment of helminth infections

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Published date: 2011
Organisations: Biological Sciences

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Local EPrints ID: 180031
URI: https://eprints.soton.ac.uk/id/eprint/180031
ISSN: 0026-895X
PURE UUID: 50bdfd2e-7e0f-42b9-9a2c-4a39dc81736e
ORCID for Anna Crisford: ORCID iD orcid.org/0000-0001-5775-643X
ORCID for Robert J. Walker: ORCID iD orcid.org/0000-0002-9031-7671
ORCID for Lindy Holden-Dye: ORCID iD orcid.org/0000-0002-9704-1217

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Date deposited: 06 Apr 2011 14:16
Last modified: 29 Oct 2019 02:11

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Contributors

Author: Anna Crisford ORCID iD
Author: Caitriona Murray
Author: Vincent O'Connor
Author: Richard J. Edwards
Author: Nina Kruger
Author: Claudia Welz
Author: Georg von Samson-Himmelstjerna
Author: Achim Harder

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