Latrotoxin Receptor Signaling Engages the UNC-13-Dependent Vesicle-Priming Pathway in C. elegans

Willson, James K.V.; Amliwala, Kiran; Davis, A. M.; Cook, A. H.; Cuttle, Matthew F.; Kriek, Neline; Hopper, Neil A.; O’Connor, Vincent; Harder, Achim; Walker, Robert J.; Holden‐Dye, Lindy

doi:10.1016/j.cub.2004.12.036

Cited by 12 publications

(25 citation statements)

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“…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%

“…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%

“…Taken together, these studies indicate that emodepside acts to inhibit neuromuscular transmission in nematodes and thus impairs the vital functions of motility, feeding, and reproduction (Willson et al, , 2004Bull et al, 2007). Mutagenesis screening for C. elegans resistant to the inhibitory effects of emodepside on locomotion identified SLO-1, a calcium-and voltage-activated potassium channel, as the major determinant of emodepside sensitivity Holden-Dye et al, 2007).…”

Section: Introductionmentioning

confidence: 85%

“…It has been shown previously that emodepside inhibits the fast coordinated pumping activity of the pharynx that occurs in the presence of the stimulatory neurotransmitter 5-HT (Willson et al, 2004). This effect is mediated presynaptically (Willson et al, 2004) and is highly dependent on the presence of neuronally expressed slo-1 . In this study, we used the pharyngeal preparation to further test the sensitivity of strains expressing either SLO-1 or KCNMA1 to emodepside by employing the transgenics we had generated that expressed either slo-1 or kcnma1 in the slo-1(js379) mutant from the native slo-1 promoter.…”

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 94%

“…In the pharyngeal system of C. elegans, slo-1 is expressed in the neural circuits but not in the pharyngeal muscle (Wang et al, 2001;Chiang et al, 2006). It has been shown previously that emodepside inhibits the fast coordinated pumping activity of the pharynx that occurs in the presence of the stimulatory neurotransmitter 5-HT (Willson et al, 2004). This effect is mediated presynaptically (Willson et al, 2004) and is highly dependent on the presence of neuronally expressed slo-1 .…”

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 98%

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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: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 85%

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 94%

Section: Structural Comparison Of Slo-1 and Kcnma1mentioning

confidence: 98%

See 3 more Smart Citations

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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Identification and evolution of latrophilin receptor gene involved in Tribolium castaneum devolopment and female fecundity

Gao

Liu

et al. 2017

Genesis

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Latrophilins (LPHs) are adhesion G-protein-coupled receptors comprising three paralogous forms (LPH-1, LPH-2, and LPH-3) and known receptors for α-latrotoxin, which are involved in growth, development, adaptability, and schizophrenia and other diseases in vertebrates. However, the functions of LPH are poorly understood in most insects. Here, phylogenetic and synteny analysis indicated that LPH-1 and LPH-3 evolved separately from a common ancestor LPH-2. Then, latrophilin (Tclph) was cloned in Tribolium castaneum, and three alternatively spliced transcripts (Tclpha, Tclphb and Tclphc) were identified. All these three Tclphs were highest expressed at the early adult stage, and strongly expressed in central nervous system of adults. Larval RNA interference (RNAi) against Tclph caused 24% adult wing abnormal, 30% insect death, and led to 100% reductions in beetle fecundity. Fecundity deficiency was rescued by reciprocal crosses with wild-type females, but not males. And dissection results revealed that 63% of dsTclph female ovaries were atrophied. Further, exon-specific RNAi illustrated that neither knockdown of Tclpha nor Tclphc resulted in development defects and reductions in beetle fecundity. Thus, it indicated that Tclphb was essential for development and female fecundity in T. castaneum. Moreover, Tclph knockdown increased the expression of the foxo, plc, and pka genes, which most likely modulated the effects of Tclph on development and reproduction in T. castaneum.

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Behavioral and transcriptomic profiling of mice null forLphn3, a gene implicated inADHDand addiction

Orsini

Setlow

DeJesus

et al. 2016

Molec Gen & Gen Med

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BackgroundThe Latrophilin 3 (LPHN3) gene (recently renamed Adhesion G protein‐coupled receptor L3 (ADGRL3)) has been linked to susceptibility to attention deficit/hyperactivity disorder (ADHD) and vulnerability to addiction. However, its role and function are not well understood as there are no known functional variants.MethodsTo characterize the function of this little known gene, we phenotyped Lphn3 null mice. We assessed motivation for food reward and working memory via instrumental responding tasks, motor coordination via rotarod, and depressive‐like behavior via forced swim. We also measured neurite outgrowth of primary hippocampal and cortical neuron cultures. Standard blood chemistries and blood counts were performed. Finally, we also evaluated the transcriptome in several brain regions.ResultsBehaviorally, loss of Lphn3 increases both reward motivation and activity levels. Lphn3 null mice display significantly greater instrumental responding for food than wild‐type mice, particularly under high response ratios, and swim incessantly during a forced swim assay. However, loss of Lphn3 does not interfere with working memory or motor coordination. Primary hippocampal and cortical neuron cultures demonstrate that null neurons display comparatively enhanced neurite outgrowth after 2 and 3 days in vitro. Standard blood chemistry panels reveal that nulls have low serum calcium levels. Finally, analysis of the transcriptome from prefrontal cortical, striatal, and hippocampal tissue at different developmental time points shows that loss of Lphn3 results in genotype‐dependent differential gene expression (DGE), particularly for cell adhesion molecules and calcium signaling proteins. Much of the DGE is attenuated with age, and is consistent with the idea that ADHD is associated with delayed cortical maturation.ConclusionsTranscriptome changes likely affect neuron structure and function, leading to behavioral anomalies consistent with both ADHD and addiction phenotypes. The data should further motivate analyses of Lphn3 function in the developmental timing of altered gene expression and calcium signaling, and their effects on neuronal structure/function during development.

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Latrotoxin Receptor Signaling Engages the UNC-13-Dependent Vesicle-Priming Pathway in C. elegans

Cited by 12 publications

References 0 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

Identification and evolution of latrophilin receptor gene involved in Tribolium castaneum devolopment and female fecundity

Behavioral and transcriptomic profiling of mice null forLphn3, a gene implicated inADHDand addiction

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