title: A family of excitatory peptide toxins from venomous crassispirine snails: using Constellation Pharmacology to assess bioactivity.
abstract: The toxinology of the crassispirine snails, a major group of venomous marine gastropods within the superfamily Conoidea, is largely unknown. Here we define the first venom peptide superfamily, the P-like crassipeptides, and show that the organization of their gene sequences is similar to conotoxin precursors. We provide evidence that one peptide family within the P-like crassipeptide superfamily includes potassium-channel (K-channel) blockers, the κP-crassipeptides. Three of these peptides were chemically synthesized (cce9a, cce9b and iqi9a). Using conventional electrophysiology, cce9b was shown to be an antagonist of both a human Kv1.1 channel isoform (Shaker subfamily of voltage-gated K channels) and a Drosophila K-channel isoform. We assessed the bioactivity of these peptides in native mammalian dorsal root ganglion neurons in culture. We demonstrate that two of these crassipeptides, cce9a and cce9b, elicited an excitatory phenotype in a subset of small-diameter capsaicin-sensitive mouse DRG neurons that were also affected by κJ-conotoxin PlXIVA (pl14a), a blocker of Kv1.6 channels. Given the vast complexity of heteromeric K-channel isoforms, this study demonstrates that the crassispirine venoms are a potentially rich source for discovering novel peptides that can help to identify and characterize the diversity of K-channel subtypes expressed in native neurons and other cell types.
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA. Electronic address: imperial@biology.utah.edu.
authors.forename: Julita S
authors.initials: JS
authors.lastname: Imperial
authors.affiliation: Marine Science Institute, University of the Philippines, Diliman, Quezon City 1101, Philippines.
authors.forename: April B
authors.initials: AB
authors.lastname: Cabang
authors.affiliation: Institute of Physiology, University of Kiel, Hermann-Rodewald-Straße 5, 24118 Kiel, Germany.
authors.forename: Jie
authors.initials: J
authors.lastname: Song
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Shrinivasan
authors.initials: S
authors.lastname: Raghuraman
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Joanna
authors.initials: J
authors.lastname: Gajewiak
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Maren
authors.initials: M
authors.lastname: Watkins
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Patrice
authors.initials: P
authors.lastname: Showers-Corneli
authors.affiliation: A.N. Severtzov Institute of Ecology and Evolution, Russian Academy of Science, Moscow, 119071 Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Fedosov
authors.affiliation: Marine Science Institute, University of the Philippines, Diliman, Quezon City 1101, Philippines.
authors.forename: Gisela P
authors.initials: GP
authors.lastname: Concepcion
authors.affiliation: Institute of Physiology, University of Kiel, Hermann-Rodewald-Straße 5, 24118 Kiel, Germany.
authors.forename: Heinrich
authors.initials: H
authors.lastname: Terlau
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Russell W
authors.initials: RW
authors.lastname: Teichert
authors.affiliation: Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA.
authors.forename: Baldomero M
authors.initials: BM
authors.lastname: Olivera
mesh_terms: D000818:Animals; D003001:Cloning, Molecular; D004330:Drosophila; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008978:Mollusk Venoms / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D010455:Peptides / Q000737:chemistry* / Q000302:isolation & purification / Q000633:toxicity; D010802:Phylogeny; D015221:Potassium Channels / Q000737:chemistry; D012908:Snails / Q000737:chemistry* / Q000235:genetics; D014981:Xenopus
chemical_list: D008978:Mollusk Venoms; D010455:Peptides; D015221:Potassium Channels
keywords: Conotoxin; Crassipeptide; Crassispirine snails; Potassium channel; cce9a; cce9b