Omega-Conotoxin
Omega-conotoxins are disulfide-rich peptides from cone snail venom that block N-type and P/Q-type voltage-gated calcium channels, with ziconotide as the approved therapeutic.
Chemical Identity
| Property | Value |
|---|---|
| Chemical Formula | Variable by conotoxin subtype |
| Molecular Weight | 2500-3500 g/mol (typical) |
| CAS Number | Variable by subtype |
| IUPAC Name | Omega-conotoxin family |
| Peptide Class | Conotoxin (Calcium Channel Blocker) |
| Origin | Conus species (cone snails) |
| Disulfide Bonds | 3 (typical cysteine knot motif) |
Structure
Omega-conotoxins are small (24-31 amino acid), highly constrained peptides from the venom of predatory cone snails (Conus species). They contain three intramolecular disulfide bonds forming a cysteine knot or inhibitor cysteine knot (ICK) motif, which confers remarkable stability against proteolysis and thermal denaturation. The cysteine framework is designated as pattern VI/VII in the conotoxin nomenclature. Key residues in the binding loops determine selectivity for calcium channel subtypes.
Mechanism of Action
Omega-conotoxins selectively block voltage-gated calcium channels (VGCCs):
- Omega-conotoxin MVIIA (ziconotide): Selective for N-type (Cav2.2) channels
- Omega-conotoxin GVIA: Highly selective for N-type channels
- Omega-conotoxin MVIIC: Blocks both N-type and P/Q-type (Cav2.1) channels
The peptides bind to the extracellular pore-forming domain of the alpha1 subunit, physically occluding the channel pore and preventing calcium influx. This blocks neurotransmitter release at presynaptic terminals.
Biological Functions
Omega-conotoxins serve a predatory function for cone snails:
- Prey immobilization: Rapid paralysis through neuromuscular blockade
- Pain pathway inhibition: Blockade of N-type channels in dorsal horn nociceptive neurons
- Envenomation: Part of a complex venom cocktail targeting multiple ion channels simultaneously
Research and Clinical Applications
- Ziconotide (omega-conotoxin MVIIA): FDA-approved intrathecal analgesic for severe chronic pain
- Research tools: Omega-conotoxins are essential for dissecting calcium channel function in neuroscience
- Pain research: Mapping N-type channel distribution in pain pathways
- Drug development: Backbone-cyclized and modified analogs in development for improved oral bioavailability
Safety and Side Effects
Omega-conotoxins cause neuromuscular paralysis and hypotension when administered systemically. Intrathecal delivery (ziconotide) avoids systemic toxicity but can cause dizziness, confusion, and psychiatric symptoms. The therapeutic window is narrow, requiring slow dose titration.
References
- Olivera, B.M., et al. (1985). Peptide neurotoxins from fish-hunting cone snails. Science, 230, 1338-1343.
- Bhatt, D.L., et al. (2013). Conotoxins as tools to understand ion channel function. Journal of Biological Chemistry, 288, 9983-9989.
Test Your Knowledge
Reinforce what you learned about Omega-Conotoxin with interactive quizzes on Wikipept.
Take a Quiz on Wikipept