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

Guest, Marcus; Bull, Kate; Walker, Robert; Amliwala, Kiran; O’Connor, Vincent; Harder, Achim; Holden‐Dye, Lindy; Hopper, Neil A.

doi:10.1016/j.ijpara.2007.05.006

Cited by 107 publications

(141 citation statements)

References 31 publications

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“…slo-1 has been shown to be widely expressed in C. elegans (Wang et al, 2001), in neurons, and in body-wall muscle. This accords with the observation that the slo-1 behavioral phenotypes of increased frequency of reversals (Wang et al, 2001;Guest et al, 2007) and erratic pharyngeal pumping (Dillon et al, 2009) were restored when a wild-type copy of slo-1 was expressed from either the native promoter or a pan-neuronal promoter. In addition, the reversal phenotype was significantly rescued by expression of slo-1 in body-wall muscle consistent with the observation that native slo-1 is also expressed in this tissue (Carre-Pierrat et al, 2006).…”

Section: Discussionsupporting

confidence: 89%

“…In control experiments, each application of 5-HT elicited a robust excitatory response, as reported previously (Willson et al, 2004;Guest et al, 2007). To quantify the level of emodepside inhibition, we compared the pharyngeal pumping frequency observed in response to 300 nM 5-HT (a submaximal concentration) (Rogers et al, 2001) before and 5 min after addition of 100 nM emodepside (Fig.…”

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 72%

“…Wild-type C. elegans initiate foraging behavior in the absence of food, characterized by forward locomotion and spontaneous reversals (Chiba and Rankin, 1990). slo-1(js379) C. elegans have a higher frequency of reversals than wild-type (Wang et al, 2001;Guest et al, 2007). Age-synchronized (L4 plus 1 day) wildtype, slo-1(js379), and transgenic C. elegans described above were assayed on 9-cm NGM plates with no food.…”

Section: Heterologous Expression Of Human Bk Channel In C Elegansmentioning

confidence: 99%

“…elegans slo-1 and Mammalian kcnma1 Rescue Behavioral Phenotypes in slo-1(js379). slo-1(js379) mutants move with similar speed and frequency of body bends compared with wild-type C. elegans, but their rate of reversals is significantly increased (Wang et al, 2001;Guest et al, 2007). To identify whether slo-1 and kcnma1 are functional orthologs, we expressed cDNAs of both genes in the slo-1(js379) mutant background from pan-neuronal (snb-1), body-wall muscle (myo-3), and the native slo-1 promoter and determined to what extent these rescued the reversal phenotype of slo-1(js379).…”

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 99%

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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: Discussionsupporting

confidence: 89%

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 72%

Section: Heterologous Expression Of Human Bk Channel In C Elegansmentioning

confidence: 99%

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 99%

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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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“…The functions of LPH1 and its homologs (LPH2 and LPH3) (3) are unclear. In Caenorhabditis elegans, the LPH1 ortholog LAT-1 plays a role in embryo morphogenesis (16) and modulation of neurotransmitter release (17,18). Null mutations in LAT-1 arrest worm development at the embryo stage (16).…”

mentioning

confidence: 99%

Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities

Silva

Lelianova

Ermolyuk

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

223

353

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Latrophilin 1 (LPH1), a neuronal receptor of α-latrotoxin, is implicated in neurotransmitter release and control of presynaptic Ca 2+ . As an "adhesion G-protein-coupled receptor," LPH1 can convert cell surface interactions into intracellular signaling. To examine the physiological functions of LPH1, we used LPH1's extracellular domain to purify its endogenous ligand. A single protein of ∼275 kDa was isolated from rat brain and termed Lasso. Peptide sequencing and molecular cloning have shown that Lasso is a splice variant of teneurin-2, a brain-specific orphan cell surface receptor with a function in neuronal pathfinding and synaptogenesis. We show that LPH1 and Lasso interact strongly and specifically. They are always copurified from rat brain extracts. Coculturing cells expressing LPH1 with cells expressing Lasso leads to their mutual attraction and formation of multiple junctions to which both proteins are recruited. Cells expressing LPH1 form chimerical synapses with hippocampal neurons in cocultures; LPH1 and postsynaptic neuronal protein PSD-95 accumulate on opposite sides of these structures. Immunoblotting and immunoelectron microscopy of purified synapses and immunostaining of cultured hippocampal neurons show that LPH1 and Lasso are enriched in synapses; in both systems, LPH1 is presynaptic, whereas Lasso is postsynaptic. A C-terminal fragment of Lasso interacts with LPH1 and induces Ca 2+ signals in presynaptic boutons of hippocampal neurons and in neuroblastoma cells expressing LPH1. Thus, LPH1 and Lasso can form transsynaptic complexes capable of inducing presynaptic Ca 2+ signals, which might affect synaptic functions.

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Target Identification and Mechanism‐Based Screening for Anthelmintics: Application of Veterinary Antiparasitic Research Programs to Search for New Antiparasitic Drugs for Human Indications

Geary

Woods

Williams

et al. 2009

Antiparasitic and Antibacterial Drug Discovery

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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

Cited by 107 publications

References 31 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

Latrophilin 1 and its endogenous ligand Lasso/teneurin-2 form a high-affinity transsynaptic receptor pair with signaling capabilities

Target Identification and Mechanism‐Based Screening for Anthelmintics: Application of Veterinary Antiparasitic Research Programs to Search for New Antiparasitic Drugs for Human Indications

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