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The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans

The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans
The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans
The cyclo-octadepsipeptide anthelmintic, emodepside, has pleiotropic effects on the behaviour of the model genetic animal Caenorhabditis elegans: it inhibits locomotion, feeding, egg-laying and slows development. Previous studies on pharyngeal muscle indicated a role for latrophilin-dependent signalling and therefore prompted the suggestion that this is a common effector of this drug’s actions. However, whilst a C. elegans functional null mutant for latrophilin (lat-1) is less sensitive to the effect of emodepside on the pharynx it remains sensitive to the inhibitory effects of emodepside on locomotion. Here we show that this is not due to functional redundancy between two C. elegans latrophilins, as the double mutant, lat-2, lat-1, also remains sensitive to the effects of emodepside on locomotion. Therefore, emodepside has latrophilin-independent effects. To define the molecular basis for this we performed a mutagenesis screen. We recovered nine alleles of slo-1, which encodes a Ca2+-activated K+ channel. These mutants were highly resistant to the inhibitory effect of emodepside on both pharyngeal and locomotor activity. The slo-1 alleles are predicted to reduce or eliminate SLO-1 signalling, suggesting that emodepside may signal through a SLO-1-dependent pathway. The observation that gain-of-function slo-1 alleles phenocopy the effects of emodepside, but are not themselves emodepside hypersensitive, favours a model whereby emodepside directly acts through a SLO-1-dependent pathway. Tissue-specific genetic rescue experiments reveal that emodepside acts through SLO-1 expressed in either body wall muscle or in neurones to inhibit locomotion. In contrast, in the pharyngeal system, emodepside acts through SLO-1 in neurones, but not muscle, to inhibit feeding. These data further inform understanding of the mode of action of emodepside and suggest that emodepside causes inhibition of feeding via a neuronal SLO-1-dependent pathway which is facilitated by LAT-1 whilst it signals through a latrophilin-independent, SLO-1-dependent pathway, in either neurones or body wall muscle, to inhibit locomotion.
anthelmintic, cyclo-octadepsipeptide, BK channel, calcium-activated potassium channel, behaviour, latrophilin, mutagenesis
0020-7519
1577-1588
Guest, Marcus
62c17f1d-014a-4e56-8a39-a9987c3abbb2
Bull, Kathryn
fd07202e-8fa2-419f-80ec-ba8e2a4db8b1
Walker, Robert J.
9368ac2d-f1e9-4bd9-a4b4-4a161c4aa140
Amliwala, Kiran
685f7867-ded3-4a25-8665-c427a04320cf
Connor, Vincent
2cf1c62e-b77a-4054-90c1-7867b76f7fe7
Harder, Achim
6bcbaba4-2209-45eb-a29f-5f1ac4476fa2
Holden-Dye, Lindy
8032bf60-5db6-40cb-b71c-ddda9d212c8e
Hopper, Neil A.
d2aed184-733b-47f6-8d74-fa1633ae6cf0
Guest, Marcus
62c17f1d-014a-4e56-8a39-a9987c3abbb2
Bull, Kathryn
fd07202e-8fa2-419f-80ec-ba8e2a4db8b1
Walker, Robert J.
9368ac2d-f1e9-4bd9-a4b4-4a161c4aa140
Amliwala, Kiran
685f7867-ded3-4a25-8665-c427a04320cf
Connor, Vincent
2cf1c62e-b77a-4054-90c1-7867b76f7fe7
Harder, Achim
6bcbaba4-2209-45eb-a29f-5f1ac4476fa2
Holden-Dye, Lindy
8032bf60-5db6-40cb-b71c-ddda9d212c8e
Hopper, Neil A.
d2aed184-733b-47f6-8d74-fa1633ae6cf0

Guest, Marcus, Bull, Kathryn, Walker, Robert J., Amliwala, Kiran, Connor, Vincent, Harder, Achim, Holden-Dye, Lindy and Hopper, Neil A. (2007) The calcium-activated potassium channel, SLO-1, is required for the action of the novel cyclo-octadepsipeptide anthelmintic, emodepside, in Caenorhabditis elegans. International Journal for Parasitology, 37 (14), 1577-1588. (doi:10.1016/j.ijpara.2007.05.006).

Record type: Article

Abstract

The cyclo-octadepsipeptide anthelmintic, emodepside, has pleiotropic effects on the behaviour of the model genetic animal Caenorhabditis elegans: it inhibits locomotion, feeding, egg-laying and slows development. Previous studies on pharyngeal muscle indicated a role for latrophilin-dependent signalling and therefore prompted the suggestion that this is a common effector of this drug’s actions. However, whilst a C. elegans functional null mutant for latrophilin (lat-1) is less sensitive to the effect of emodepside on the pharynx it remains sensitive to the inhibitory effects of emodepside on locomotion. Here we show that this is not due to functional redundancy between two C. elegans latrophilins, as the double mutant, lat-2, lat-1, also remains sensitive to the effects of emodepside on locomotion. Therefore, emodepside has latrophilin-independent effects. To define the molecular basis for this we performed a mutagenesis screen. We recovered nine alleles of slo-1, which encodes a Ca2+-activated K+ channel. These mutants were highly resistant to the inhibitory effect of emodepside on both pharyngeal and locomotor activity. The slo-1 alleles are predicted to reduce or eliminate SLO-1 signalling, suggesting that emodepside may signal through a SLO-1-dependent pathway. The observation that gain-of-function slo-1 alleles phenocopy the effects of emodepside, but are not themselves emodepside hypersensitive, favours a model whereby emodepside directly acts through a SLO-1-dependent pathway. Tissue-specific genetic rescue experiments reveal that emodepside acts through SLO-1 expressed in either body wall muscle or in neurones to inhibit locomotion. In contrast, in the pharyngeal system, emodepside acts through SLO-1 in neurones, but not muscle, to inhibit feeding. These data further inform understanding of the mode of action of emodepside and suggest that emodepside causes inhibition of feeding via a neuronal SLO-1-dependent pathway which is facilitated by LAT-1 whilst it signals through a latrophilin-independent, SLO-1-dependent pathway, in either neurones or body wall muscle, to inhibit locomotion.

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More information

Published date: December 2007
Keywords: anthelmintic, cyclo-octadepsipeptide, BK channel, calcium-activated potassium channel, behaviour, latrophilin, mutagenesis
Organisations: Biological Sciences

Identifiers

Local EPrints ID: 55908
URI: http://eprints.soton.ac.uk/id/eprint/55908
ISSN: 0020-7519
PURE UUID: d850a93c-4735-4429-a3f4-1df688fe9553
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 Aug 2008
Last modified: 17 Dec 2019 02:04

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Contributors

Author: Marcus Guest
Author: Kathryn Bull
Author: Kiran Amliwala
Author: Vincent Connor
Author: Achim Harder
Author: Neil A. Hopper

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