Effects Of SO-3, A Novel Conotoxin In Pain Control, On Lon Channels

Conotoxins (CTX) are a diverse set of small, conformationally constrained peptides from Conus snail venoms, most of which contain multiple disulfide bonds and can selectively target a specific voltage-gated ion channel, ligand-gated ion channel, or G-protein-coupled receptor. These diversified toxins are generally categorized into several superfamilies and/or families based on their characteristic arrangements of cysteine residues and pharmacological actions, ω-, κ-, μO- and δ-CTX share the same framework (C-C-CC-C-C) of O-superfamily, but differ in their molecular targets. Both μO- and δ-CTX selectively target voltage-dependent sodium channels (VDSCs), while ω- and κ-CTX selectively target voltage-dependent calcium channels (VDCCs) and voltage-dependent potassium channels (VDPCs), respectively. The individual peptides in one CTX family may selectively target a diverse set of different molecular isoforms within the same ion channel family. For example, ω-CTX MVⅡA and MVⅡC, both derived from Conus magus, have high identity in sequence, but have quite different selectivity: MVⅡA is highly selective for N-type VDCCs, whereas MVⅡC is more selective for the P/Q-type. On the other hand, peptides derived from different cone snail species, although their conopeptide sequences vary largely except the cysteine framework, may act on the same ion channel subtype, as both ω-conotoxin MVⅡA and GVIA can block the same N-type VDCCs.Due to the highly pharmacological potency and target selectivity of CTX, they have attracted extensive attentions with their potentials to be developed as new tools for ion channel research as well as for the treatment and diagnosis of neurological diseases. One of these peptides, co-CTX MVIIA (MVIIA), has passed extensive human clinical trials and was approved by the United States Food and Drug Administration for the treatment of intractable chronic pain. A new 25-residue conopeptide, SO-3, was identified by us previously from the venom of Conus striatus, a fish-eating snail inhabiting the South China Sea. SO-3 contains the same cysteine framework as O-superfamily CTX and shows 56% sequence identity with SVIB, a P/Q-type VDCCs blocker derived from Conusstriatus. and 72% with MVIIA, an N-type VDCCs blocker. Further bioactivity evaluation on the synthetic SO-3 showed that SO-3 is a potent analgesic agent with similar effects to MVIIA. However, the ion channel target of SO-3 is still unclear. Here, we observed the effects of SO-3 on voltage-dependent ion channels by using the whole-cell patch clamping techniques.1 Effects of SO-3 on voltage-dependent ion channels in cultured hippocampal neuronsVoltage-dependent sodium currents (7Na), delayed rectifier potassium currents (/k(dr>), transient outward potassium currents (7^