Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes
Lewis, Richard J., Nielsen, Katherine J., Craik, David J., Loughnan, Marion L., Adams, Denise A., Sharpe, Iain A., Luchian, Tudor, Adams, David J., Bond, Trudy, Thomas, Linda, Jones, Alun, Matheson, Jodi-Lea, Drinkwater, Roger, Andrews, Peter R., and Alewood, Paul F. (2000) Novel omega-conotoxins from Conus catus discriminate among neuronal calcium channel subtypes. Journal of Biological Chemistry, 275 (45). pp. 35335-35344.
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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 (Refereed Research - C1)|
|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 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 Research Support, Non-U.S. Gov't Sequence Homology, Amino Acid Sequence Homology, Nucleic Acid Snails Spectrum Analysis, Mass Time Factors Vas Deferens/metabolism Xenopus laevis omega-Conotoxins/chemistry/genetics/*metabolism/pharmacology|
© 2000 Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, Inc., Bethesda, MD, 20814.
Reproduced with permission from American Society for Biochemistry and Molecular Biology.
|Date Deposited:||08 Sep 2006|
|FoR Codes:||06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology @ 50%
06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060105 Cell Neurochemistry @ 50%
|SEO Codes:||92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920199 Clinical Health (Organs, Diseases and Abnormal Conditions) not elsewhere classified @ 100%|
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