SO‐3, a new O‐superfamily conopeptide derived from Conus striatus, selectively inhibits N‐type calcium currents in cultured hippocampal neurons

1 Whole‐cell currents in cultured hippocampal neurons were recorded to investigate the effects of SO‐3, a new O‐superfamily conopeptide derived from Conus striatus, on voltage‐sensitive channels. 2 SO‐3 had no effect on voltage‐sensitive sodium currents, delayed rectifier potassium currents, and transient outward potassium currents. 3 Similar to the selective N‐type calcium channel blocker ω‐conotoxin MVIIA (MVIIA), SO‐3 could concentration‐dependently inhibit the high voltage‐activated (HVA) calcium currents (ICa). 4 MVIIA(3 μM), 10 μM nimodipine, and 0.5 μM ω‐agatoxin IVA (Aga) could selectively block the N‐, L‐, and P/Q‐type ICa, which contributed ∼32, ∼38, and ∼21% of the HVA currents in hippocampal neurons, respectively. About 31% of the total HVA currents were inhibited by 3 μM SO‐3. SO‐3 (3 μM) and 3 μM MVIIA inhibited the overlapping components of HVA currents, whereas no overlapping component was inhibited by 3 μM SO‐3 and 10 μM nimodipine, or by 3 μM SO‐3 and 0.5 μM Aga. Also, 3 μM SO‐3 had no effect on R‐type currents. 5 SO‐3 had less inhibitory effects on non‐N‐type HVA currents than MVIIA at higher concentrations (30 and 100 μM). 6 The inhibitory effects of SO‐3 and MVIIA on HVA currents were almost fully reversible. However, the recovery from block by MVIIA was more rapid than recovery from block by SO‐3. 7 It is concluded that SO‐3 is a new ω‐conotoxin selectively targeting N‐type voltage‐sensitive calcium channels. Considering the significance of N‐type calcium channels for pain transduction, SO‐3 may have therapeutic potential as a novel analgesic agent. British Journal of Pharmacology (2005) 145, 728–739. doi:10.1038/sj.bjp.0706223