Editors' ChoicePhysiology

Venom induces insulin shock

Science Signaling  27 Jan 2015:
Vol. 8, Issue 361, pp. ec19
DOI: 10.1126/scisignal.aaa7481

Predatory cone snails use powerful cocktails of toxins to capture prey and for defense. Many cone snails stab prey with a high-speed poison barb, but others secrete venom to disable prey before engulfing it within a large net-like, protruding mouth. Safavi-Hemami et al. found insulin homologs in the venoms of two species of cone snail that release toxins into the water to slow or disorient prey. Transcriptomic and cDNA library analyses revealed the presence of three insulin homologs (Con-Ins G1, G2, and G3) in the venom glands of Conus geographus. Vertebrate and molluscan insulins differ in size and in the number of conserved cysteine residues that mediate disulfide bonding in the mature, processed form of the protein. Con-Ins G2 was similar to other molluscan insulin proteins, whereas Con-Ins G1 and Con-Ins G3 were predicted to produce mature proteins more similar to vertebrate insulins than to molluscan insulins. Analysis of cDNA libraries identified vertebrate-like insulins in the venom gland of C. tulipa, another species that secretes venom to stun prey. Mass spectrometry analysis of C. geographus venom revealed that several variants of Con-Ins G1 and Con-Ins G3, but not any forms of Con-Ins G2, were present in venom and had posttranslational modifications similar to those typical of previously characterized conotoxins. Chemically synthesized Con-Ins G1 (sCon-Ins G1) reduced blood glucose when injected into hyperglycemic adult zebrafish and reduced locomotor activity of zebrafish larvae when added to the water, indicating that sCon-Ins G1 was absorbed through the gills. Insulin, along with the neurotoxins contained in the venom cocktail, therefore likely contributes to prey capture by C. geophraphus and C. tulipa. The weaponized insulins are smaller than most vertebrate insulins and lack sequences homologous to those important for fine-tuning vertebrate insulin signaling, suggesting that they are specialized for inducing hypoglycemia. These potent forms of insulin could be investigated as potential therapies for diabetes.

H. Safavi-Hemami, J. Gajewiak, S. Karanth, S. D. Robinson, B. Ueberheide, A. D. Douglass, A. Schlegel, J. S. Imperial, M. Watkins, Pradip K. Bandyopadhyay, M. Yandell, Q. Li, A. W. Purcell, R. S. Norton, L. Ellgaard, B. M. Olivera, Specialized insulin is used for chemical warfare by fish-hunting cone snails. Proc. Natl. Acad. Sci. U.S.A. 10.1073/pnas.1423857112 (2015). [PubMed]