Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes
G protein-coupled receptors (GPCRs) are established drug targets. Despite their considerable appeal as targets for next-generation anthelmintics, poor understanding of their diversity and function in parasitic helminths has thwarted progress towards GPCR-targeted anti-parasite drugs. This study faci...
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Format: | Article |
Language: | English |
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Elsevier
2018-04-01
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Series: | International Journal for Parasitology: Drugs and Drug Resistance |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211320717301331 |
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doaj-6c49fc116d124b2ca6df6512d296b7ea |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Paul McVeigh Erin McCammick Paul McCusker Duncan Wells Jane Hodgkinson Steve Paterson Angela Mousley Nikki J. Marks Aaron G. Maule |
spellingShingle |
Paul McVeigh Erin McCammick Paul McCusker Duncan Wells Jane Hodgkinson Steve Paterson Angela Mousley Nikki J. Marks Aaron G. Maule Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes International Journal for Parasitology: Drugs and Drug Resistance |
author_facet |
Paul McVeigh Erin McCammick Paul McCusker Duncan Wells Jane Hodgkinson Steve Paterson Angela Mousley Nikki J. Marks Aaron G. Maule |
author_sort |
Paul McVeigh |
title |
Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes |
title_short |
Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes |
title_full |
Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes |
title_fullStr |
Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes |
title_full_unstemmed |
Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum Platyhelminthes |
title_sort |
profiling g protein-coupled receptors of fasciola hepatica identifies orphan rhodopsins unique to phylum platyhelminthes |
publisher |
Elsevier |
series |
International Journal for Parasitology: Drugs and Drug Resistance |
issn |
2211-3207 |
publishDate |
2018-04-01 |
description |
G protein-coupled receptors (GPCRs) are established drug targets. Despite their considerable appeal as targets for next-generation anthelmintics, poor understanding of their diversity and function in parasitic helminths has thwarted progress towards GPCR-targeted anti-parasite drugs. This study facilitates GPCR research in the liver fluke, Fasciola hepatica, by generating the first profile of GPCRs from the F. hepatica genome. Our dataset describes 147 high confidence GPCRs, representing the largest cohort of GPCRs, and the largest set of in silico ligand-receptor predictions, yet reported in any parasitic helminth. All GPCRs fall within the established GRAFS nomenclature; comprising three glutamate, 135 rhodopsin, two adhesion, five frizzled, one smoothened, and one secretin GPCR. Stringent annotation pipelines identified 18 highly diverged rhodopsins in F. hepatica that maintained core rhodopsin signatures, but lacked significant similarity with non-flatworm sequences, providing a new sub-group of potential flukicide targets. These facilitated identification of a larger cohort of 76 related sequences from available flatworm genomes, representing new members of existing groups (PROF1/Srfb, Rho-L, Rho-R, Srfa, Srfc) of flatworm-specific rhodopsins. These receptors imply flatworm specific GPCR functions, and/or co-evolution with unique flatworm ligands, and could facilitate the development of exquisitely selective anthelmintics. Ligand binding domain sequence conservation relative to deorphanised rhodopsins enabled high confidence ligand-receptor matching of seventeen receptors activated by acetylcholine, neuropeptide F/Y, octopamine or serotonin. RNA-Seq analyses showed expression of 101 GPCRs across various developmental stages, with the majority expressed most highly in the pathogenic intra-mammalian juvenile parasites. These data identify a broad complement of GPCRs in F. hepatica, including rhodopsins likely to have key functions in neuromuscular control and sensory perception, as well as frizzled and adhesion/secretin families implicated, in other species, in growth, development and reproduction. This catalogue of liver fluke GPCRs provides a platform for new avenues into our understanding of flatworm biology and anthelmintic discovery. Keywords: Anthelmintic, Deorphanization, Flukicide, Genome, Invertebrate, Nervous system, Neuropeptide, RNA-Seq |
url |
http://www.sciencedirect.com/science/article/pii/S2211320717301331 |
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doaj-6c49fc116d124b2ca6df6512d296b7ea2020-11-24T20:58:45ZengElsevierInternational Journal for Parasitology: Drugs and Drug Resistance2211-32072018-04-018187103Profiling G protein-coupled receptors of Fasciola hepatica identifies orphan rhodopsins unique to phylum PlatyhelminthesPaul McVeigh0Erin McCammick1Paul McCusker2Duncan Wells3Jane Hodgkinson4Steve Paterson5Angela Mousley6Nikki J. Marks7Aaron G. Maule8Parasitology & Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK; Corresponding author.Parasitology & Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UKParasitology & Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UKParasitology & Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UKInstitute of Infection and Global Health, University of Liverpool, Liverpool, UKInstitute of Integrative Biology, University of Liverpool, Liverpool, UKParasitology & Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UKParasitology & Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UKParasitology & Pathogen Biology, The Institute for Global Food Security, School of Biological Sciences, Queen's University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UKG protein-coupled receptors (GPCRs) are established drug targets. Despite their considerable appeal as targets for next-generation anthelmintics, poor understanding of their diversity and function in parasitic helminths has thwarted progress towards GPCR-targeted anti-parasite drugs. This study facilitates GPCR research in the liver fluke, Fasciola hepatica, by generating the first profile of GPCRs from the F. hepatica genome. Our dataset describes 147 high confidence GPCRs, representing the largest cohort of GPCRs, and the largest set of in silico ligand-receptor predictions, yet reported in any parasitic helminth. All GPCRs fall within the established GRAFS nomenclature; comprising three glutamate, 135 rhodopsin, two adhesion, five frizzled, one smoothened, and one secretin GPCR. Stringent annotation pipelines identified 18 highly diverged rhodopsins in F. hepatica that maintained core rhodopsin signatures, but lacked significant similarity with non-flatworm sequences, providing a new sub-group of potential flukicide targets. These facilitated identification of a larger cohort of 76 related sequences from available flatworm genomes, representing new members of existing groups (PROF1/Srfb, Rho-L, Rho-R, Srfa, Srfc) of flatworm-specific rhodopsins. These receptors imply flatworm specific GPCR functions, and/or co-evolution with unique flatworm ligands, and could facilitate the development of exquisitely selective anthelmintics. Ligand binding domain sequence conservation relative to deorphanised rhodopsins enabled high confidence ligand-receptor matching of seventeen receptors activated by acetylcholine, neuropeptide F/Y, octopamine or serotonin. RNA-Seq analyses showed expression of 101 GPCRs across various developmental stages, with the majority expressed most highly in the pathogenic intra-mammalian juvenile parasites. These data identify a broad complement of GPCRs in F. hepatica, including rhodopsins likely to have key functions in neuromuscular control and sensory perception, as well as frizzled and adhesion/secretin families implicated, in other species, in growth, development and reproduction. This catalogue of liver fluke GPCRs provides a platform for new avenues into our understanding of flatworm biology and anthelmintic discovery. Keywords: Anthelmintic, Deorphanization, Flukicide, Genome, Invertebrate, Nervous system, Neuropeptide, RNA-Seqhttp://www.sciencedirect.com/science/article/pii/S2211320717301331 |