Analgesic omega-conotoxins CVIE and CVIF selectively and voltage dependently block recombinant and native N-type calcium channels

Berecki, 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. and Adams, D. J. (2009) Analgesic omega-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.109.058834


Author Berecki, 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.
Title Analgesic omega-conotoxins CVIE and CVIF selectively and voltage dependently block recombinant and native N-type calcium channels
Formatted title
Analgesic ω-Conotoxins CVIE and CVIF Selectively and Voltage-Dependently Block Recombinant and Native N-Type Calcium Channels
Journal name Molecular Pharmacology   Check publisher's open access policy
ISSN 0026-895X
1521-0111
Publication date 2009-11-05
Year available 2009
Sub-type Article (original research)
DOI 10.1124/mol.109.058834
Volume 77
Issue 2
Start page 139
End page 148
Total pages 10
Place of publication Bethesda, MD, United States
Publisher American Society for Pharmacology & Experimental Therapeutics
Collection year 2010
Language eng
Subject C1
1109 Neurosciences
920111 Nervous System and Disorders
860899 Human Pharmaceutical Products not elsewhere classified
0304 Medicinal and Biomolecular Chemistry
Formatted abstract
Neuronal (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.
Keyword Conotoxins
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 28 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 30 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Wed, 20 Jan 2010, 10:04:53 EST by Debra McMurtrie on behalf of Queensland Brain Institute