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Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes

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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. L., Drinkwater, R., Andrews, P. R. and Alewood, P. F. (2000) Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. Journal of biological chemistry, 275 (45). pp. 35335-44. ISSN 0021-9258 (Print)0021-9258

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Article Link(s): https://doi.org/10.1074/jbc.M002252200

Abstract

omega-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 omega-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 omega-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, omega-conotoxins CVID and MVIIA had similar potencies to inhibit current through central (alpha(1B-d)) and peripheral (alpha(1B-b)) splice variants of the rat N-type calcium channels when coexpressed with rat beta(3) in Xenopus oocytes. However, the potency of CVID and MVIIA increased when alpha(1B-d) and alpha(1B-b) were expressed in the absence of rat beta(3), an effect most pronounced for CVID at alpha(1B-d) (up to 540-fold) and least pronounced for MVIIA at alpha(1B-d) (3-fold). The novel selectivity of CVID may have therapeutic implications. (1)H 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.

Item Type:Article
Additional Information:Open access pdf attached
Keywords:Alternative Splicing Amino Acid Sequence Animals Base Sequence Brain/metabolism Calcium Channel Blockers/pharmacology Calcium Channels/*metabolism Chromatography, High Pressure Liquid Cloning, Molecular DNA, Complementary/metabolism Dose-Response Relationship, Drug Electrophysiology Hydrogen Bonding Ions Magnetic Resonance Spectroscopy Male Mass Spectrometry Models, Molecular Molecular Sequence Data Neurons/*metabolism Oocytes/metabolism Peptide Biosynthesis Peptides/chemistry Protein Binding Protein Conformation Protein Isoforms Protein Structure, Secondary RNA, Messenger/metabolism Rats Rats, Wistar Sequence Homology, Amino Acid Sequence Homology, Nucleic Acid Snails Time Factors Vas Deferens/metabolism Xenopus laevis omega-Conotoxins/chemistry/genetics/*metabolism/pharmacology
Subjects:Science > Biology > Biochemistry
Science > Biology > Molecular Biology
Science > Microbiology > Microorganisms in the animal body
Deposited On:15 Oct 2020 02:23
Last Modified:15 Oct 2020 02:23

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