title: Specialized insulin is used for chemical warfare by fish-hunting cone snails.
abstract: More than 100 species of venomous cone snails (genus Conus) are highly effective predators of fish. The vast majority of venom components identified and functionally characterized to date are neurotoxins specifically targeted to receptors, ion channels, and transporters in the nervous system of prey, predators, or competitors. Here we describe a venom component targeting energy metabolism, a radically different mechanism. Two fish-hunting cone snails, Conus geographus and Conus tulipa, have evolved specialized insulins that are expressed as major components of their venoms. These insulins are distinctive in having much greater similarity to fish insulins than to the molluscan hormone and are unique in that posttranslational modifications characteristic of conotoxins (hydroxyproline, γ-carboxyglutamate) are present. When injected into fish, the venom insulin elicits hypoglycemic shock, a condition characterized by dangerously low blood glucose. Our evidence suggests that insulin is specifically used as a weapon for prey capture by a subset of fish-hunting cone snails that use a net strategy to capture prey. Insulin appears to be a component of the nirvana cabal, a toxin combination in these venoms that is released into the water to disorient schools of small fish, making them easier to engulf with the snail's distended false mouth, which functions as a net. If an entire school of fish simultaneously experiences hypoglycemic shock, this should directly facilitate capture by the predatory snail.
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112; Department of Biology, Copenhagen Biocenter, DK-2200 Copenhagen, Denmark; safavihelena@gmail.com olivera@biology.utah.edu.
authors.forename: Helena
authors.initials: H
authors.lastname: Safavi-Hemami
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112;
authors.forename: Joanna
authors.initials: J
authors.lastname: Gajewiak
authors.affiliation: University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT 84112; Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112;
authors.forename: Santhosh
authors.initials: S
authors.lastname: Karanth
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia;
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Robinson
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University Langone Medical Center, New York, NY 10016;
authors.forename: Beatrix
authors.initials: B
authors.lastname: Ueberheide
authors.affiliation: Department of Neurobiology and Anatomy, University of Utah, Salt Lake City, UT 84112;
authors.forename: Adam D
authors.initials: AD
authors.lastname: Douglass
authors.affiliation: University of Utah Molecular Medicine Program, University of Utah School of Medicine, Salt Lake City, UT 84112; Department of Internal Medicine, Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, UT 84112; Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112;
authors.forename: Amnon
authors.initials: A
authors.lastname: Schlegel
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112;
authors.forename: Julita S
authors.initials: JS
authors.lastname: Imperial
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112;
authors.forename: Maren
authors.initials: M
authors.lastname: Watkins
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112;
authors.forename: Pradip K
authors.initials: PK
authors.lastname: Bandyopadhyay
authors.affiliation: Eccles institute of Human Genetics, University of Utah, Salt Lake City, UT 84112; The Utah Science Technology and Research Initiative Center for Genetic Discovery, University of Utah, Salt Lake City, UT 84112; and.
authors.forename: Mark
authors.initials: M
authors.lastname: Yandell
authors.affiliation: Eccles institute of Human Genetics, University of Utah, Salt Lake City, UT 84112;
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, VIC 3800, Australia.
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Purcell
authors.affiliation: Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia;
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Norton
authors.affiliation: Department of Biology, Copenhagen Biocenter, DK-2200 Copenhagen, Denmark;
authors.forename: Lars
authors.initials: L
authors.lastname: Ellgaard
authors.affiliation: Department of Biology, University of Utah, Salt Lake City, UT 84112; safavihelena@gmail.com olivera@biology.utah.edu.
authors.forename: Baldomero M
authors.initials: BM
authors.lastname: Olivera
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D052078:Conus Snail / Q000737:chemistry* / Q000502:physiology*; D007328:Insulin / Q000032:analysis / Q000138:chemical synthesis / Q000235:genetics* / Q000378:metabolism; D008387:Marine Toxins / Q000737:chemistry* / Q000378:metabolism; D013058:Mass Spectrometry; D008969:Molecular Sequence Data; D011235:Predatory Behavior / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D013045:Species Specificity; D015027:Zebrafish / Q000378:metabolism*
chemical_list: D007328:Insulin; D008387:Marine Toxins
keywords: cone snails; conotoxins; insulin shock; nirvana cabal; venom