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          Institute: MPI für experimentelle Medizin     Collection: MCN     Display Documents



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ID: 292163.0, MPI für experimentelle Medizin / MCN
A novel conotoxin inhibitor of Kv1.6 channel and nAChR subtypes defines a new superfamily of conotoxins
Authors:Imperial, Julita S.; Bansal, Paramjit S.; Alewood, Paul F.; Daly, Norelle L.; Craik, David J.; Sporning, Annett; Terlau, Heinrich; Lopez-Vera, Estuardo; Bandyopadhyay, Pradip K.; Olivera, Baldomero M.
Language:English
Date of Publication (YYYY-MM-DD):2006-07
Title of Journal:Biochemistry
Journal Abbrev.:Biochemistry
Volume:45
Issue / Number:27
Start Page:8331
End Page:8340
Review Status:Peer-review
Audience:Experts Only
Abstract / Description:Using assay-directed fractionation of the venom from the vermivorous cone snail Conus planorbis, we isolated a new conotoxin, designated p114a, with potent activity at both nicotinic acetylcholine receptors and a voltage-gated potassium channel subtype. p114a contains 25 amino acid residues with an amidated C-terminus, an elongated N-terminal tail (six residues), and two disulfide bonds (1-3, 2-4 connectivity) in a novel framework distinct from other conotoxins. The peptide was chemically synthesized, and its three-dimensional structure was demonstrated to be well-defined, with an R-helix and two 3(10)-helices present. Analysis of a cDNA clone encoding the prepropeptide precursor of p114a revealed a novel signal sequence, indicating that p114a belongs to a new gene superfamily, the J-conotoxin superfamily. Five additional peptides in the J-superfamily were identified. Intracranial injection of p114a in mice elicited excitatory symptoms that included shaking, rapid circling, barrel rolling, and seizures. Using the oocyte heterologous expression system, p114a was shown to inhibit both a K+ channel subtype (Kv1.6, IC50) 1.59 mu M) and neuronal (IC50 = 8.7 mu M for alpha 3 beta 4) and neuromuscular (IC50 = 0.54 mu M for alpha 1 beta 1 is an element of delta) subtypes of the nicotinic acetylcholine receptor ( nAChR). Similarities in sequence and structure are apparent between the middle loop of p114a and the second loop of a number of alpha-conotoxins. This is the first conotoxin shown to affect the activity of both voltage-gated and ligand-gated ion channels.
Free Keywords:NICOTINIC ACETYLCHOLINE-RECEPTORS; CONUS-VENOM PEPTIDES; SHAKER K+ CHANNEL; ALPHA-CONOTOXIN; POTASSIUM CHANNELS; SCORPION TOXIN; CONVERGENT EVOLUTION; CHEMICAL-SYNTHESIS; NMR STRUCTURE; MARINE SNAIL
External Publication Status:published
Document Type:Article
Communicated by:Heinrich Terlau
Affiliations:MPI für experimentelle Medizin/MCN
Identifiers:ISSN:0006-2960 [ID No:1]
ISI:000238726800015 [ID No:2]
ISI:000238726800015 [ID No:3]
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