Publication Details

Lewis, R. J., Nielsen, K. J., Craik, D. J., Loughnan, M. L., Adams, D. A., Sharpe, I. A., Luchian, T., Adams, D. J., Bond, T., Thomas, L., Jones, A., Matheson, J., Drinkwater, R., Andrews, P. R. & Alewood, P. F. (2000). Novel ω-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. Journal of Biological Chemistry, 275 (45), 35335-35344.


ω-Conotoxins selective for N-type calcium channels are useful in the management of severe pain. In an attempt to expand the therapeutic potential of this class, four new ω-conotoxins (CVIA-D) have been discovered in the venom of the piscivorous cone snail, Conus catus, using assay-guided fractionation and gene cloning. Compared with other ω-conotoxins, CVID has a novel loop 4 sequence and the highest selectivity for N-type over P/Q-type calcium channels in radioligand binding assays. CVIA-D also inhibited contractions of electrically stimulated rat vas deferens. In electrophysiological studies, ω-conotoxins CVID and MVIIA had similar potencies to inhibit current through central (α(1B-d)) and peripheral (α(1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat β3 in Xenopus oocytes. However, the potency of CVID and MVIIA increased when α(1B-d) and α(1B-b) were expressed in the absence of rat β3, an effect most pronounced for CVID at α(1B-d) (up to 540-fold) and least pronounced for MVIIA at α(1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. 1H NMR studies reveal that CVID possesses a combination of unique structural features, including two hydrogen bonds that stabilize loop 2 and place loop 2 proximal to loop 4, creating a globular surface that is rigid and well defined.



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