A novel conotoxin inhibitor of Kv1.6 channel and nAChR subtypes defines a new superfamily of conotoxins

Imperial, J. S., Bansal, P. S., Alewood, P. F., Daly, N. L., Craik, D., Sporning, A., Terlau, H., Lopez-Vera, E., Bandyopadhyay, P. K. and Olivera, B. M. (2006) A novel conotoxin inhibitor of Kv1.6 channel and nAChR subtypes defines a new superfamily of conotoxins. Biochemistry, 45 27: 8331-8340. doi:10.1021/bi060263r

Author Imperial, J. S.
Bansal, P. S.
Alewood, P. F.
Daly, N. L.
Craik, D.
Sporning, A.
Terlau, H.
Lopez-Vera, E.
Bandyopadhyay, P. K.
Olivera, B. M.
Title A novel conotoxin inhibitor of Kv1.6 channel and nAChR subtypes defines a new superfamily of conotoxins
Journal name Biochemistry   Check publisher's open access policy
ISSN 0006-2960
Publication date 2006
Sub-type Article (original research)
DOI 10.1021/bi060263r
Volume 45
Issue 27
Start page 8331
End page 8340
Total pages 10
Editor R. N. Armstrong
Place of publication Washington, D.C.
Publisher American Chemical Society
Collection year 2006
Language eng
Subject C1
250302 Biological and Medical Chemistry
780105 Biological sciences
Abstract 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.
Keyword Chemistry
Molecular Biology
Cell Biology
Biochemistry & Molecular Biology
Nicotinic Acetylcholine-receptors
Conus-venom Peptides
Shaker K+ Channel
Potassium Channels
Scorpion Toxin
Convergent Evolution
Nmr Structure
Marine Snail
Q-Index Code C1

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Created: Wed, 15 Aug 2007, 08:18:07 EST