Analgesic ω-conotoxins CVIE and CVIF selectively and voltage-dependently block recombinant and native n-type calcium channels

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dc.contributor.authorBerecki, Gen_AU
dc.contributor.authorMotin, Len_AU
dc.contributor.authorHaythornthwaite, Aen_AU
dc.contributor.authorVink, Sen_AU
dc.contributor.authorBansal, PSen_AU
dc.contributor.authorDrinkwater, Ren_AU
dc.contributor.authorWang, CIen_AU
dc.contributor.authorMoretta, Men_AU
dc.contributor.authorLewis, RJen_AU
dc.contributor.authorAlewood, PFen_AU
dc.contributor.authorChristie, MJen_AU
dc.contributor.authorAdams, DJen_AU
dc.date.accessioned2010-05-07T01:26:26Zen_AU
dc.date.available2010-05-07T01:26:26Zen_AU
dc.date.issued2010-02-01en_AU
dc.date.statistics2010-02-01en_AU
dc.description.abstractNeuronal (N)-type Ca2+ channel-selective ω-conotoxins have emerged as potential new drugs for the treatment of chronic pain. In this study, two new ω-conotoxins, CVIE and CVIF, were discovered from a Conus catus cDNA library. Both conopeptides potently displaced 125I-GVIA binding to rat brain membranes. In Xenopus laevis oocytes, CVIE and CVIF potently and selectively inhibited depolarization-activated Ba2+ currents through recombinant N-type (α1B-b/α2δ1/β3) Ca2+ channels. Recovery from block increased with membrane hyperpolarization, indicating that CVIE and CVIF have a higher affinity for channels in the inactivated state. The link between inactivation and the reversibility of ω-conotoxin action was investigated by creating molecular diversity in β subunits: N-type channels with β2a subunits almost completely recovered from CVIE or CVIF block, whereas those with β3 subunits exhibited weak recovery, suggesting that reversibility of the ω-conotoxin block may depend on the type of β-subunit isoform. In rat dorsal root ganglion sensory neurons, neither peptide had an effect on low-voltage-activated T-type channels but potently and selectively inhibited high voltage-activated N-type Ca2+ channels in a voltage-dependent manner. In rat spinal cord slices, both peptides reversibly inhibited excitatory monosynaptic transmission between primary afferents and dorsal horn superficial lamina neurons. Homology models of CVIE and CVIF suggest that ω-conotoxin/voltage-gated Ca2+ channel interaction is dominated by ionic/electrostatic interactions. In the rat partial sciatic nerve ligation model of neuropathic pain, CVIE and CVIF (1 nM) significantly reduced allodynic behavior. These N-type Ca2+ channel-selective ω-conotoxins are therefore useful as neurophysiological tools and as potential therapeutic agents to inhibit nociceptive pain pathways. © 2010, American Society for Pharmacology and Experimental Therapeutics (ASPET)en_AU
dc.identifier.citationBerecki, G., Motin, L., Haythornthwaite, A., Vink, S., Bansal, P., Drinkwater, R., Wang, C. I., Moretta, M., Lewis, R. J., Alewood, P. F., Christie, M. J., & Adams, D. J. Analgesic ω-conotoxins CVIE and CVIF selectively and voltage-dependently block recombinant and native n-type calcium channels. Molecular Pharmacology, 77(2), 139-148. doi.10.1124/mol.109.058834en_AU
dc.identifier.govdoc1664en_AU
dc.identifier.issn0026-895Xen_AU
dc.identifier.issue2en_AU
dc.identifier.journaltitleMolecular Pharmacologyen_AU
dc.identifier.pagination139-148en_AU
dc.identifier.urihttp://dx.doi.org/10.1124/mol.109.058834en_AU
dc.identifier.urihttp://apo.ansto.gov.au/dspace/handle/10238/1641en_AU
dc.identifier.volume77en_AU
dc.language.isoenen_AU
dc.publisherAmerican Society for Pharmacology and Experimental Therapeutics (ASPET)en_AU
dc.subjectCalciumen_AU
dc.subjectTherapyen_AU
dc.subjectDrugsen_AU
dc.subjectPainen_AU
dc.subjectElectric potentialen_AU
dc.subjectNerve cellsen_AU
dc.titleAnalgesic ω-conotoxins CVIE and CVIF selectively and voltage-dependently block recombinant and native n-type calcium channelsen_AU
dc.typeJournal Articleen_AU
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