Related Experiment Video
Updated: Jun 18, 2026
Establishing a Mouse Model of a Pure Small Fiber Neuropathy with the Ultrapotent Agonist of Transient Receptor Potential Vanilloid Type 1
Published on: February 13, 2018
Analgesic (omega)-conotoxins CVIE and CVIF selectively and voltage-dependently block recombinant and native N-type
G Berecki1, L Motin, A Haythornthwaite
1Department of Physiology and Pharmacology, University of Calgary, Alberta, T2N4N1 Canada. gberecki@ucalgary.ca
Abstract:
Neuronal (N)-type Ca(2+) channel-selective omega-conotoxins have emerged as potential new drugs for the treatment of chronic pain. In this study, two new omega-conotoxins, CVIE and CVIF, were discovered from a Conus catus cDNA library. Both conopeptides potently displaced (125)I-GVIA binding to rat brain membranes. In Xenopus laevis oocytes, CVIE and CVIF potently and selectively inhibited depolarization-activated Ba(2+) currents through recombinant N-type (alpha1(B-b)/alpha(2)delta1/beta(3)) Ca(2+) 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 omega-conotoxin action was investigated by creating molecular diversity in beta subunits: N-type channels with beta(2a) subunits almost completely recovered from CVIE or CVIF block, whereas those with beta(3) subunits exhibited weak recovery, suggesting that reversibility of the omega-conotoxin block may depend on the type of beta-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 Ca(2+) 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 omega-conotoxin/voltage-gated Ca(2+) 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 Ca(2+) channel-selective omega-conotoxins are therefore useful as neurophysiological tools and as potential therapeutic agents to inhibit nociceptive pain pathways.
Insights
Two novel omega-conotoxins, CVIE and CVIF, selectively block N-type Ca(2+) channels, offering potential for treating chronic pain by inhibiting nociceptive pathways.
Area of Science:
- Neuroscience
- Pharmacology
- Molecular Biology
Background:
- Neuronal (N)-type Ca(2+) channels are crucial in pain signaling.
- Omega-conotoxins are peptides with potential therapeutic applications for pain management.
Purpose of the Study:
- To discover and characterize novel omega-conotoxins targeting N-type Ca(2+) channels.
- To investigate the therapeutic potential of these conotoxins in neuropathic pain models.
Main Methods:
- Discovery of CVIE and CVIF from Conus catus cDNA library.
- In vitro assays using oocytes and brain membranes to assess channel binding and inhibition.
- Electrophysiology in sensory neurons and spinal cord slices.
- In vivo testing in a rat model of neuropathic pain.
Main Results:
- CVIE and CVIF selectively inhibit N-type Ca(2+) channels.
- Conotoxin reversibility is influenced by beta-subunit isoforms.
- Peptides reduced allodynia in a neuropathic pain model.
- Homology modeling suggests electrostatic interactions in channel binding.
Conclusions:
- CVIE and CVIF are potent and selective N-type Ca(2+) channel blockers.
- These conotoxins serve as valuable neurophysiological tools.
- CVIE and CVIF show promise as therapeutic agents for nociceptive pain.
Related Concept Videos
01:30Ligand-Gated Ion Channel Receptor: Gating Mechanism
01:25Antianginal Drugs: Calcium Channel Blockers and Ranolazine
CCBs, a diverse class that includes dihydropyridines (nifedipine) and diphenylalkylamines (verapamil and diltiazem), exert their effect by blocking calcium channels in cardiac and smooth muscle cells. This...
01:18Antihypertensive Drugs: Action of Calcium Channel Blockers
01:26Voltage-gated Ion Channels
Generally, all voltage-gated ion channels have a 'voltage-sensing domain' that spans the lipid bilayer. The charged residues in the sensor move in response to the membrane potential changes that open the channel allowing ions movement. There are several types of...
01:26Voltage-gated Ion Channels
Generally, all voltage-gated ion channels have a 'voltage-sensing domain' that spans the lipid bilayer. The charged residues in the sensor move in response to the membrane potential changes that open the channel allowing ions movement. There are several types of...
01:26Directly Acting Muscle Relaxants: Dantrolene and Botulinum Toxin
The binding of dantrolene to the RYR1...