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 ( I Ca ). 4 MVIIA(3  μ M) , 10  μ M nimodipine, and 0.5  μ M ω ‐agatoxin IVA (Aga) could selectively block the N‐, L‐, and P/Q‐type I Ca , 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  μ M SO‐3. SO‐3 (3  μ M ) and 3  μ M MVIIA inhibited the overlapping components of HVA currents, whereas no overlapping component was inhibited by 3  μ M SO‐3 and 10  μ M nimodipine, or by 3  μ M SO‐3 and 0.5  μ M Aga. Also, 3  μ M 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  μ M ). 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