Ca Channel Inhibitors: Conotoxin

Brief Introduction of Ca Channel Inhibitors: Conotoxin

Conotoxins, a kind of bioactive peptide toxin obtained from the marine gastropod mollusk conus. They can selectively act on ion channels and other protein receptors, thus affecting nerve conduction and producing different physiological effects. Conotoxins are small peptides with a length of 10-40 amino acid residues that contain multiple disulfide bridges. According to their target sites, they can be classified into α, ω, μ, δ, κ, and μ/ ν and other types. The ω-conotoxins specifically block voltage-sensitive calcium channels (VGCCs). Conotoxins have been proven to have potential applications in a variety of pathological conditions and have become a powerful therapeutic tool.

Calcium entry mediated by VGCCs is the initial trigger for the release of neurotransmitters from presynaptic nerve terminals. VGCCs are important targets for the treatment of pain, stroke, epilepsy, migraine, and hypertension due to their important role in calcium signaling.

Mechanisms of Conotoxin Inhibition of VGCCs

Multiple and complex pathophysiological mechanisms are responsible for the development and maintenance of chronic pain. Altered N-type VGCC function in sensory neurons has been implicated as one of these mechanisms, suggesting that VGCCs inhibitors or modulators could be developed into useful drugs to treat neuropathic pain. The main mechanism that ω-conotoxins specifically blocks VGCCs is by blocking the channel pore, which is accomplished by tight binding of the toxin to the channel pore. This binding reduces calcium influx through the channels presumably by occluding the pore.

Fig.1 Putative mechanisms of action of VGCC-inhibiting conotoxins. (Mohammadi, 2015)

Therapeutic Use of Conotoxins

It is well known that the conotoxins could selectively bind closely to relevant molecular targets which is an important advantage of these marine conopeptides. Another advantage of conotoxins is the diversity of targets, as they can act on ion channels, several G-protein coupled receptors, and ligand-gated receptors. These properties make them excellent candidates for the development of new biological compounds and derivatives to combat pathologies, such as pain, stroke, and convulsive diseases.

The ω-conotoxins are the most widely used conus peptide family in neuroscience. They have been intensively studied to inhibit neurotransmitter release and treat inflammatory and chronic neuropathic conditions. Typically, neuronal Ca_V channels have potential to be used as targets for treatments of pain and the selectivity of conotoxins for these channels makes conopeptides a valuable therapeutic tool. Owing to their stable structure, small size, and target specificity, conotoxins are considered an ideal molecular probe for target validation and peptide drug discovery.

The wide applications of conotoxins require improvements to enhance their transport across the blood-brain barrier and modification to improve their chemical stability.

Fig. 2 Main pharmacological properties of conotoxins. (Mir, 2016)

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References

1. Mohammadi, S.A.; et al. Conotoxin Interactions with α9α10-nAChRs: Is the α9α10-Nicotinic Acetylcholine Receptor an Important Therapeutic Target for Pain Management? Toxins (Basel). 2015, 7: 3916-32.
2. Mir, R.; et al. Conotoxins: Structure, Therapeutic Potential, and Pharmacological Applications. Curr Pharm Des. 2016, 22: 582-9.