Discovery and characterization of the short kappaA-conotoxins: a novel subfamily of excitatory conotoxins.
We have characterized the defining members of a novel subfamily of excitatory conotoxins, the short kappaA-conotoxins (kappaA(S)-conotoxins). kappaA-conotoxins PIVE and PIVF (kappaA-PIVE and kappaA-PIVF) were purified from Conus purpurascens venom. Both peptides elicited excitatory activity upon injection into fish. kappaA-PIVE was synthesized for further characterization. The excitatory effects of kappaA-PIVE in vivo were dose dependent, causing hyperactivity at low doses and rapid immobilization at high doses, symptomatic of a type of excitotoxic shock. Consistent with these observations, kappaA-PIVE caused repetitive action potentials in frog motor axons in vitro. Similar results have been reported for other structurally distinct conotoxin families; such peptides appear to be required by most fish-hunting cone snails for the rapid immobilization of prey. Unexpected structure-function relationships were revealed between these peptides and two families of homologous conotoxins: the alphaA-conotoxins (muscle nAChR antagonists) and kappaA-conotoxins (excitotoxins), which all share a common arrangement of cysteine residues (CC-C-C-C-C). Biochemically, the kappaA(S)-conotoxins more closely resemble the alphaA(S)-conotoxins than the other kappaA-conotoxin subfamily, the long kappaA-conotoxins (kappaA(L)-conotoxins); however, kappaA(S)- and alphaA(S)-conotoxins produce different physiological effects. In contrast, the kappaA(S)-and kappaA(L)-conotoxins that diverge in several biochemical characteristics are clearly more similar in their physiological effects.
Teichert
Russell W
RW
Department of Biology, University of Utah, 257 South 1400 East, Salt Lake City, UT 84112, USA. teichert@biology.utah.edu
Jacobsen
Richard
R
Terlau
Heinrich
H
Yoshikami
Doju
D
Olivera
Baldomero M
BM
D000595:Amino Acid Sequence; D000818:Animals; D001681:Biological Assay; D001921:Brain / Q000187:drug effects; D002851:Chromatography, High Pressure Liquid; D020916:Conotoxins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D052078:Conus Snail; D004305:Dose-Response Relationship, Drug; D006054:Goldfish; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D011894:Rana pipiens; D013329:Structure-Activity Relationship; D014981:Xenopus
D020916:Conotoxins; D009498:Neurotoxins