title: Inhibition of cholinergic pathways in Drosophila melanogaster by α-conotoxins.
abstract: Nicotinic acetylcholine receptors (nAChRs) play a pivotal role in synaptic transmission of neuronal signaling pathways and are fundamentally involved in neuronal disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In vertebrates, cholinergic pathways can be selectively inhibited by α-conotoxins; we show that in the model organism Drosophila, the cholinergic component of the giant fiber system is inhibited by α-conotoxins MII, AuIB, BuIA, EI, PeIA, and ImI. The injection of 45 pmol/fly of each toxin dramatically decreases the response of the giant fiber to dorsal longitudinal muscle (GF-DLM) connection to 20 ± 13.9% for MII; 26 ± 13.7% for AuIB, 12 ± 9.9% for BuIA, 30 ± 11.3% for EI, 1 ± 1% for PeIA, and 34 ± 15.4% for ImI. Through bioassay-guided fractionation of the venom of Conus brunneus, we found BruIB, an α-conotoxin that inhibits Drosophila nicotinic receptors but not its vertebrate counterparts. GF-DLM responses decreased to 43.7 ± 8.02% on injection of 45 pmol/fly of BruIB. We manipulated the Dα7 nAChR to mimic the selectivity of its vertebrate counterpart by placing structurally guided point mutations in the conotoxin-binding site. This manipulation rendered vertebrate-like behavior in the Drosophila system, enhancing the suitability of Drosophila as an in vivo tool to carry out studies related to human neuronal diseases. .
authors.affiliation: *Department of Chemistry and Biochemistry and Department of Biological Sciences, Florida Atlantic University, Boca Raton, Florida, USA; and Health Innovations Research Institute, RMIT University, Melbourne, Victoria, Australia.
authors.forename: Mari D
authors.initials: MD
authors.lastname: Heghinian
authors.affiliation: *Department of Chemistry and Biochemistry and Department of Biological Sciences, Florida Atlantic University, Boca Raton, Florida, USA; and Health Innovations Research Institute, RMIT University, Melbourne, Victoria, Australia.
authors.forename: Monica
authors.initials: M
authors.lastname: Mejia
authors.affiliation: *Department of Chemistry and Biochemistry and Department of Biological Sciences, Florida Atlantic University, Boca Raton, Florida, USA; and Health Innovations Research Institute, RMIT University, Melbourne, Victoria, Australia.
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.affiliation: *Department of Chemistry and Biochemistry and Department of Biological Sciences, Florida Atlantic University, Boca Raton, Florida, USA; and Health Innovations Research Institute, RMIT University, Melbourne, Victoria, Australia.
authors.forename: Tanja A
authors.initials: TA
authors.lastname: Godenschwege
authors.affiliation: *Department of Chemistry and Biochemistry and Department of Biological Sciences, Florida Atlantic University, Boca Raton, Florida, USA; and Health Innovations Research Institute, RMIT University, Melbourne, Victoria, Australia mari@fau.edu.
authors.forename: Frank
authors.initials: F
authors.lastname: Marí
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D001665:Binding Sites; D018678:Cholinergic Agents / Q000494:pharmacology; D020916:Conotoxins / Q000494:pharmacology*; D052078:Conus Snail / Q000737:chemistry; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D005260:Female; D015726:Giant Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008958:Models, Molecular; D008969:Molecular Sequence Data; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D009865:Oocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D011487:Protein Conformation; D017386:Sequence Homology, Amino Acid; D009435:Synaptic Transmission / Q000187:drug effects*; D014982:Xenopus laevis / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D018678:Cholinergic Agents; D020916:Conotoxins; D018733:Nicotinic Antagonists; D010446:Peptide Fragments; C098872:alpha-conotoxin MII; D064569:alpha7 Nicotinic Acetylcholine Receptor; D000109:Acetylcholine
keywords: Conus brunneus; giant fiber system; nicotinic acetylcholine receptors; synaptic transmission