Disruption of aminergic signalling reveals novel compounds with distinct inhibitory effects on mosquito reproduction, locomotor function and survival

Fuchs, Silke; Rende, Ermelinda; Crisanti, Andrea; Nolan, Tony

doi:10.1038/srep05526

Cited by 49 publications

(43 citation statements)

References 77 publications

(63 reference statements)

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“…It is a significant melanin precursor of quinones which are essential for exoskeleton pigmentation and hardening of the cuticle (Hultmark, 1993;Christensen et al, 2005). More importantly, DOPA is the primary production of catecholamines (such as dopamine, N-β-alanyldopamine [NBAD], N-acetyldopamine [NADA]) that effect locomotor function and survival (Budnik & White, 1987, 1988Fuchs et al, 2014). These two unambiguous functions are reported in both insects and mammals.…”

Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9‐mediated Tyrosine hydroxylase knockout resulting in larval lethality in Agrotis ipsilon

et al. 2018

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Tyrosine hydroxylase (TH) is involved in insect melanin and the catecholamine biosynthesis pathway. TH as an enzyme catalyzing the conversion of tyrosine to 3,4‐dihydroxyphenylalanine is the first step reaction in the pathway. Although TH has been proven to affect the pigmentation of the epidermis and development in many insects, there is no report about physiological function of the TH gene in Agrotis ipsilon. Here we cloned the TH gene from A. ipsilon. Semi‐quantitative real‐time polymerase chain reaction (PCR) analysis showed that AiTH was expressed at all development stages. Moreover, its high expression levels in the head and epidermis suggest that it is mainly related to pigment deposition and insect development. Then, we used the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated protein 9 system to target the AiTH gene: deletion events were detected at the target sites. Compared with the control group, a few mutants with the phenomenon of narrowing in the egg shell and embryos can develop but cannot hatch; the other hatched embryos were seriously dehydrated after hatching and died within the first day. Quantitative real‐time PCR analysis revealed that TH was down‐regulated in AiTH mutants. Here, our work demonstrated that AiTH plays an important role in growth and development of newly hatched larvae; meanwhile, it would be a promising target to explore a control strategy for A. ipsilon.

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Section: Introductionmentioning

confidence: 99%

CRISPR/Cas9‐mediated Tyrosine hydroxylase knockout resulting in larval lethality in Agrotis ipsilon

et al. 2018

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“…Molecular approaches, including genome sequencing efforts, have identified more than 100 GPCRs within the genomes of several arthropod vector species (Hill et al, 2002;Nene et al, 2007;Arensburger et al, 2010;Kirkness et al, 2010). Among the GPCR superfamily, the biogenic amine receptors are of particular interest because of their crucial roles in insect physiology and behavior (Hauser et al, 2006;Fuchs et al, 2014). For example, the biogenic amine dopamine and its receptors are implicated in a variety of arthropod behaviors, including arousal (Kume et al, 2005), locomotion (Yellman et al, 1997;Draper et al, 2007;Mustard et al, 2010), and olfactory learning (Kim et al, 2007;Riemensperger et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Evaluation ofAaDOP2 Receptor Antagonists Reveals Antidepressants and Antipsychotics as Novel Lead Molecules for Control of the Yellow Fever Mosquito,Aedes aegypti

Conley

Meyer

Nuss

et al. 2014

J Pharmacol Exp Ther

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The yellow fever mosquito, Aedes aegypti, vectors disease-causing agents that adversely affect human health, most notably the viruses causing dengue and yellow fever. The efficacy of current mosquito control programs is challenged by the emergence of insecticideresistant mosquito populations, suggesting an urgent need for the development of chemical insecticides with new mechanisms of action. One recently identified potential insecticide target is the A. aegypti D 1 -like dopamine receptor, AaDOP2. The focus of the present study was to evaluate AaDOP2 antagonism both in vitro and in vivo using assay technologies with increased throughput. The in vitro assays revealed AaDOP2 antagonism by four distinct chemical scaffolds from tricyclic antidepressant or antipsychotic chemical classes, and elucidated several structure-activity relationship trends that contributed to enhanced antagonist potency, including lipophilicity, halide substitution on the tricyclic core, and conformational rigidity. Six compounds displayed previously unparalleled potency for in vitro AaDOP2 antagonism, and among these, asenapine, methiothepin, and cis-(Z)-flupenthixol displayed subnanomolar IC 50 values and caused rapid toxicity to A. aegypti larvae and/or adults in vivo. Our study revealed a significant correlation between in vitro potency for AaDOP2 antagonism and in vivo toxicity, suggesting viability of AaDOP2 as an insecticidal target. Taken together, this study expanded the repertoire of known AaDOP2 antagonists, enhanced our understanding of AaDOP2 pharmacology, provided further support for rational targeting of AaDOP2, and demonstrated the utility of efficiency-enhancing in vitro and in vivo assay technologies within our genome-to-lead pipeline for the discovery of next-generation insecticides.

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“…Tyramine and octopamine can be involved in melanin production (Fuchs et al . ). As well as protecting against ultraviolet exposure, melanin can bind to metal ions (Gallas et al .…”

Section: Discussionmentioning

confidence: 97%

“…Ammonia metabolism intermediates were affected (through glutamine, citrulline, arginine and asparagine), as was polyamine biosynthesis (through cadaverine and putrescine) and neurotransmission and modulation (3-hydroxytyramine, 3-methoxytyramine, phenethylamine, tyramine, octopamine and dihydroxyphenylalanine). Tyramine and octopamine can be involved in melanin production (Fuchs et al 2014). As well as protecting against ultraviolet exposure, melanin can bind to metal ions (Gallas et al 1999;Szpoganicz et al 2002).…”

Section: Other Amine-containing Metabolitesmentioning

confidence: 99%

Detecting copper toxicity in sediments: from the subindividual level to the population level

Jeppe

Yang

Long

et al. 2016

Journal of Applied Ecology

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Summary Sediments accumulate chemicals that can be toxic to biota and often contribute to aquatic ecosystem decline. Measuring mortality in laboratory‐bred organisms is a common way to assess sediment toxicity. However, mortality‐based responses of resilient laboratory organisms may not reflect indigenous macroinvertebrate responses, which can be relatively more sensitive to sediment toxicants. A possible solution is to also measure responses at the subindividual level. Several organism responses to sediment copper toxicity were assessed in a field‐based microcosm. Responses of laboratory‐bred chironomids and snails deployed in microcosms were compared at subindividual (metabolomic and gene expression), individual (survival and dry weight) and population (reproduction) levels, and contrasted to the abundance of colonizing macroinvertebrates in the microcosms. Colonizing macroinvertebrate abundance showed a range of sensitivities based on EC50 (effect dose 50% change). Chironomidae made up 94·5% of the microcosm macroinvertebrates, with Paratanytarsus the most sensitive genus (EC50: 89 mg kg−1 copper) and Procladius the least sensitive (EC50: 681 mg kg−1). Survival of laboratory‐bred organisms was the least sensitive response, comparable to decreased abundance of the least sensitive macroinvertebrate. Juvenile production in the snail, Potamopyrgus antipodarum, was the most sensitive population‐level response (EC50: 121 mg kg−1), in contrast the snail Physella acuta was relatively more tolerant (EC50: 298 mg kg−1). Changes in subindividual responses (gene expression and metabolite abundance) in laboratory‐bred chironomid, Chironomus tepperi, were evident at 60 mg kg−1. These changes likely reflect the direct effects of copper exposure and represent metal‐specific responses. Synthesis and applications. We showed that copper toxicity in sediments could be readily detected through changes in gene expression and metabolites in laboratory‐bred chironomids exposed in field‐based microcosms. These responses were more sensitive than mortality, and detected copper levels that caused microcosm chironomid populations to decline. These novel approaches will provide managers with new tools to better assess sediment toxicity.

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Disruption of aminergic signalling reveals novel compounds with distinct inhibitory effects on mosquito reproduction, locomotor function and survival

Cited by 49 publications

References 77 publications

CRISPR/Cas9‐mediated Tyrosine hydroxylase knockout resulting in larval lethality in Agrotis ipsilon

CRISPR/Cas9‐mediated Tyrosine hydroxylase knockout resulting in larval lethality in Agrotis ipsilon

Evaluation ofAaDOP2 Receptor Antagonists Reveals Antidepressants and Antipsychotics as Novel Lead Molecules for Control of the Yellow Fever Mosquito,Aedes aegypti

Detecting copper toxicity in sediments: from the subindividual level to the population level

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